β-cyclodextrin (β-CD), with a lipophilic inner cavity and hydrophilic outer surface, interacts with a large variety of non-polar guest molecules to form non-covalent inclusion complexes. Conjugation of β-CD onto biomacromolecules can form physically-crosslinked hydrogel networks upon mixing with a guest molecule. Herein describes the development and characterization of self-healing, thermo-responsive hydrogels, based on host-guest inclusion complexes between alginate-graft-β-CD and Pluronic® F108 (poly(ethylene glycol)-b-poly(propylene glycol)-b-poly(ethylene glycol)). The mechanics, flow characteristics, and thermal response were contingent on the polymer concentrations, and the host-guest molar ratio. Transient and reversible physical crosslinking between host and guest polymers governed self-assembly, allowing flow under shear stress, and facilitating complete recovery of the material properties within a few seconds of unloading. The mechanical properties of the dual-crosslinked, multi-stimuli responsive hydrogels were tuned as high as 30 kPa at body temperature, and are advantageous for biomedical applications such as drug delivery and cell transplantation.

Moderate to weak mechanical properties limit the use of naturally-derived tissue sealants for dynamic medical applications, e.g., sealing a lung leak. To overcome these limitations, we developed visible-light crosslinked alginate-based hydrogels, as either non-adhesive methacrylated alginate (Alg-MA) hydrogel controls, or oxidized Alg-MA (Alg-MA-Ox) tissue adhesive tissue sealants, which form covalent bonds with extracellular matrix (ECM) proteins. Our study investigated the potential for visible-light crosslinked Alg-MA-Ox hydrogels to serve as effective surgical tissue sealants for dynamic in vivo systems. The Alg-MA-Ox hydrogels were designed to be an injectable system, curable in situ. Burst pressure experiments were conducted on a custom-fabricated burst pressure device using constant air flow; burst pressure properties and adhesion characteristics correlated with the degrees of methacrylation and oxidation. In summary, visible light crosslinked Alg-MA-Ox hydrogel tissue sealants form effective seals over critically-sized defects, and maintain pressures up to 50 mm Hg.

Poly(vinyl alcohol) (PVA) is a synthetic, biocompatible polymer that has been widely studied for use in bioengineered tissue scaffolds due to its relatively high strength, creep resistance, water retention, and porous structure. However, PVA hydrogels traditionally exhibit low percent elongation and energy dissipation. PVA material and mechanical properties can be fine-tuned by controlling the physical, non-covalent crosslinks during hydrogel formation through various techniques; PVA scaffolds were modified with gelatin, a natural collagen derivative also capable of forming reversible hydrogen bonds. Blending in gelatin and poly(ethylene glycol) (PEG) with PVA prior to solidification formed a highly organized hydrogel with improved toughness and dynamic elasticity. Theta-gels were formed from the solidification of warm solutions and the phase separation of high molecular weight gelatin and PVA from a low molecular PEG porogen upon cooling. While PVA-gelatin hydrogels can be synthesized in this manner, the hydrogels exhibited low toughness with increased elasticity. Thus, theta-gels were additionally processed using cryo-gel fabrication techniques, which involved freezing theta-gels, lyophilizing and rehydrating. The result was a stronger, more resilient material. We hypothesized that the increased formation of physical hydrogen bonds between the PVA and gelatin allowed for the combination of a stiffer material with energy dissipation characteristics. Rheological data suggested significant changes in the storage moduli of the new PVA-gelatin theta-cryo-gels. Elastic modulus, strain to failure, hysteresis and resilience were studied through uniaxial tension and dynamic mechanical analysis in compression. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of interest There are no conflicts to declare.

Injury to the connective tissue that lines the lung, the pleura, or to the lung itself can occur from many causes including trauma or surgery, as well as lung diseases or cancers. To address current limitations for patching lung injuries, to stop air or fluid leaks, an adherent hydrogel sealant patch system was developed, based on methacrylated alginate (AMA) and AMA di-aldehyde (AMA-DA) blends, which is capable of sealing damaged tissues and sustaining physiological pressures. Methacrylation of alginate hydroxyl groups rendered the polysaccharide capable of photo-crosslinking when mixed with an eosin Y-based photo-initiator system, and exposed to visible green light. Oxidation of alginate yields functional aldehyde groups capable of imine bond formation with proteins found in many tissues. The alginate-based patch system was rigorously tested on a custom burst pressure testing device. Blending of non-oxidized material with oxidized (aldehyde modified) alginates yielded patches with improved burst pressure performance, and decreased delamination as compared with pure AMA. Human mesothelial cell (MeT-5A) viability and cytotoxicity were retained when cultured with the hydrogel patches. The release and bioactivity of doxorubicin-encapsulated sub-microspheres enabled the fabrication of drug-eluting adhesive patches, and were effective in decreasing human lung cancer cell (A549) viability.

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Intervertebral disk degeneration is one of the most significant contributors to low back pain. Thus, there is significant interest in designing new treatments and nucleus pulposus (NP) tissue replacements. Herein, the authors propose a biosynthetic material, comprised of a polyvinyl alcohol (PVA) and gelatin theta-gel, as an acellular NP tissue replacement. Theta-gels form during the solidification of PVA and gelatin (phase I), and the phase separation of a disklike short-chain polyethylene glycol (PEG, phase II). The PVA concentration and weight ratio of PVA to PEG were optimized, in order to achieve mechanical properties resembling NP tissue. Mechanical and material properties were analyzed for the PVA-gelatin theta-gels under static and dynamic conditions. Cyclic stress-strain testing demonstrated the theta-gels' ability to relax and perform properly under dynamic loading. Altering the molecular weight and concentration of the theta-gel constituents allows for a tunable material that can match a variety of native tissue properties.

The limitations of commercially available tissue sealants have resulted in the need for a new tissue adhesives with adequate adhesion, improved mechanical properties, and innocuous degradation products. To address current limitations, a visible light cross-linking method for the preparation of hydrogel tissue sealants, based on natural polymers (chitosan or alginate), is presented. Water-soluble chitosan was generated via modification with vinyl groups. To form hydrogels, alginate and chitosan were cross-linked by green light illumination, with or without the use of a bifunctional cross-linker. Evaluation of the mechanical properties through rheological characterization demonstrated an increased viscosity of polymer blends, and differences in shear moduli despite similar gelation points upon photo-cross-linking. A comparative study on the burst pressure properties of liquid versus solid material applications was performed to determine if the tissue sealants can perform under physiological lung pressures and beyond using different application methods. Higher burst pressure values were obtained for the sealants applied as a liquid compared to the solid application. The hydrogel tissue sealants revealed no cytotoxic effects toward primary human mesenchymal stem cells. This is the first report of a direct comparison between hydrogel tissue sealants of the same formulation applied in liquid versus solid form.

Poly(vinyl alcohol) (PVA), a synthetic, nontoxic polymer, is widely studied for use as a biomedical hydrogel due to its structural and physicomechanical properties. Depending on the synthesis method, PVA hydrogels can exhibit a range of selected characteristics-strength, creep resistance, energy dissipation, degree of crystallinity, and porosity. While the structural integrity and behavior of the hydrogel can be finetuned, common processing techniques result in a brittle, linear elastic material. In addition, PVA lacks functionality to engage and participate in cell adhesion, which can be a limitation for integrating PVA materials with tissue in situ. Thus, there is a need to further engineer PVA hydrogels to optimize its physicomechanical properties while enhancing cell adhesion and bioactivity. While the inclusion of gelatin into PVA hydrogels has been shown to impart cell-adhesive properties, the optimization of the mechanical properties of PVA-gelatin blends has not been studied in the context of traditional PVA hydrogel processing techniques. The incorporation of poly(ethylene glycol) with PVA prior to solidification forms an organized, cell instructive hydrogel with improved stiffness. The effect of cryo-processing, i.e., freezethaw (FT) cycling was elucidated by comparing 1 FT and 8 FT theta-cryo-gels and cryo-gels. To confirm the viability of the gels, human mesenchymal stem cell (hMSC) protein and sulfated glycosaminoglycan assays were performed to verify the nontoxicity and influence on hMSC differentiation. We have devised an elastic PVA-gelatin hydrogel utilizing the theta-gel and cryo-gel processing techniques, resulting in a stronger, more elastic material with greater potential as a scaffold for complex tissues.