Poly(vinyl alcohol), PVA, and physical hydrogels derived thereof have an excellent safety profile and a successful history of biomedical applications. However, these materials are hardly in the focus of biomedical research, largely due to poor opportunities in nano- and micro-scale design associated with PVA hydrogels in their current form. In this review we aim to demonstrate that with PVA, a (sub)molecular control over polymer chemistry translates into fine-tuned supramolecular association of chains and this, in turn, defines macroscopic properties of the material. This nano- to micro- to macro- translation of control is unique for PVA and can now be accomplished using modern tools of macromolecular design. We believe that this strategy affords functionalized PVA physical hydrogels which meet the demands of modern nanobiotechnology and have a potential to become an indispensable tool in the design of biomaterials.

The ex vivo growth of implantable hepatic or cardiac tissue remains a challenge and novel approaches are highly sought after. We report an approach to use liposomes embedded within multilayered films as drug deposits to deliver active cargo to adherent cells. We verify and characterize the assembly of poly(l-lysine) (PLL)/alginate, PLL/poly(l-glutamic acid), PLL/poly(methacrylic acid) (PMA), and PLL/cholesterol-modified PMA (PMAc) films, and assess the myoblast and hepatocyte adhesion to these coatings using different numbers of polyelectrolyte layers. The assembly of liposome-containing multilayered coatings is monitored by QCM-D, and the films are visualized using microscopy. The myoblast and hepatocyte adhesion to these films using PLL/PMAc or poly(styrenesulfonate) (PSS)/poly(allyl amine hydrochloride) (PAH) as capping layers is evaluated. Finally, the uptake of fluorescent lipids from the surface by these cells is demonstrated and compared. The activity of this liposome-containing coating is confirmed for both cell lines by trapping the small cytotoxic compound thiocoraline within the liposomes. It is shown that the biological response depends on the number of capping layers, and is different for the two cell lines when the compound is delivered from the surface, while it is similar when administered from solution. Taken together, we demonstrate the potential of liposomes as drug deposits in multilayered films for surface-mediated drug delivery.

Many biomedical applications benefit from responsive polymer coatings. The properties of poly(dopamine) (PDA) films can be affected by codepositing dopamine (DA) with the temperature-responsive polymer poly(N-isopropylacrylamide) (pNiPAAm). We characterize the film assembly at 24 and 39 °C using DA and aminated or carboxylated pNiPAAm by a quartz crystal microbalance with dissipation monitoring (QCM-D), X-ray photoelectron spectroscopy, UV-vis, ellipsometry, and atomic force microscopy. It was found that pNiPAAm with both types of end groups are incorporated into the films. We then identified a temperature-dependent adsorption behavior of proteins and liposomes to these PDA and pNiPAAm containing coatings by QCM-D and optical microscopy. Finally, a difference in myoblast cell response was found when these cells were allowed to adhere to these coatings. Taken together, these fundamental findings considerably broaden the potential biomedical applications of PDA films due to the added temperature responsiveness.

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Hydrogel biomaterials based on poly(vinyl alcohol), PVA, have an extensive history of biomedical applications, yet in their current form suffer from significant shortcomings, such as a lack of mechanism of biodegradation and poor opportunities in controlled drug release. We investigate physical hydrogels of PVA as surface-adhered materials and present biodegradable matrices equipped with innovative tools in substrate-mediated drug release. Toward the final goal, PVA chains with narrow polydispersities (1.1-1.2) and molecular weights of 5, 10, and 28 kDa are synthesized via controlled radical polymerization (RAFT). These molecular weights are shown to be suitably high to afford robust hydrogel matrices and at the same time suitably low to allow gradual erosion of the hydrogels with kinetics of degradation controlled via polymer macromolecular characteristics. For opportunities in controlled drug release, hydrogels are equipped with enzymatic cargo to achieve an in situ conversion of externally added prodrug into a final product, thus giving rise to surface-adhered enzymatic microreactors. Hydrogel-mediated enzymatic activity was investigated as a function of polymer molecular weight and concentration of solution taken for assembly of hydrogels. Taken together, we present, to the best of our knowledge, the first example of bioresorbable physical hydrogel based on PVA with engineered opportunities in substrate-mediated enzymatic activity and envisioned utility in surface-mediated drug delivery and tissue engineering.

Physical hydrogels based on poly(vinyl alcohol), PVA, have an excellent safety profile and a successful history of biomedical applications. However, highly inhomogeneous and macroporous internal organization of these hydrogels as well as scant opportunities in bioconjugation with PVA have largely ruled out micro- and nanoscale control and precision in materials design and their use in (nano)biomedicine. To address these shortcomings, herein we report on the assembly of PVA physical hydrogels via "salting-out", a noncryogenic method. To facilitate sample visualization and analysis, we employ surface-adhered structured hydrogels created via microtransfer molding. The developed approach allows us to assemble physical hydrogels with dimensions across the length scales, from ∼100 nm to hundreds of micrometers and centimeter sized structures. We determine the effect of the PVA molecular weight, concentration, and "salting out" times on the hydrogel properties, i.e., stability in PBS, swelling, and Young's modulus using exemplary microstructures. We further report on RAFT-synthesized PVA and the functionalization of polymer terminal groups with RITC, a model fluorescent low molecular weight cargo. This conjugated PVA-RITC was then loaded into the PVA hydrogels and the cargo concentration was successfully varied across at least 3 orders of magnitude. The reported design of PVA physical hydrogels delivers methods of production of functionalized hydrogel materials toward diverse applications, specifically surface mediated drug delivery.

tissue engineering scaffolds in order to allow for more complex tissue to be cultured. [ 7 ] SMDD can be employed in two different manners: either by releasing the cargo into the surrounding media, such as the blood-stream, or by delivering the therapeutic compound to the cells adhered to the surface. In the latter case, the creation of a polymer coating which promotes both cell adhesion and proliferation is of paramount importance. To date, the sequential deposition of interacting polymer layers to create polymer thin fi lms appears to stand out since it is a versatile, inexpensive yet effi cient technique to assemble advanced coatings. [ 8 ] Successful delivery of macromolecular cargo, e.g., oligonucleotides [ 9 ] or proteins, [ 10 ] from a surface has already been documented including the implementation in vivo. However, SMDD of small therapeutic compounds still remains a challenge, and its success is limited to specifi c examples such as the use of drug-polymer conjugates [ 11 ] or the immobilization within a carrier ( e.g. , liposomes, [ 12 ] micelles, [ 13 ] or cyclodextrins). [ 14 ] We recently reported the uptake of fl uorescent lipids by myoblast cells from a liposome-containing thin fi lm of PDA. [ 15 ] Similarly, bulk hydrogels loaded with drug-containing smaller components in the form of microparticles, [ 16 ] liposomes, [ 17 ] polymersomes, [ 18 ] or micelles, [ 19 ] are termed "composite hydrogels" and were considered to gain an enhanced control over the cargo retention and release. However, to the best of our knowledge, surface-adhered composite hydrogels and their utility in SMDD has never been considered and is presented herein for the fi rst time.As sub-compartments for PVA hydrogels, we chose polymersomes, [ 20 ] colloidal vessels which self-assemble from amphiphilic block copolymers with a well-documented Surface-mediated drug delivery (SMDD) is an approach which aims to administer therapeutics to adhering or suspension cells from implantable devices or from tissue engineering scaffolds. Herein is reported the proof of concept for polymersome-aided trapping of the cytotoxic hydrophobic compound thiocoraline in a physical poly(vinyl alcohol) (PVA) hydrogel matrix and the subsequent viability of myoblast cells cultured on this surfaceadhered composite hydrogel. The ABA triblock copolymer, poly( N -acryloyl morpholine)-block -poly(cholesteryl acrylate)-block -poly( N -acryloyl morpholine) (PNAM-b -PChA-b -PNAM), is synthesized, and the self-assembly of this polymer into polymersomes is shown. The polymersomes are loaded with the model cargo fl uorescein in order to visualize the entrapping of the small payload in this composite hydrogel. To render the PVA hydrogels cell adhesive, a poly(dopamine) (PDA) coating is successfully applied to the biointerface. Finally, to demonstrate the feasibility that active cargo can be entrapped and yield a cell response, the composite hydrogels are loaded with the cytotoxic depsipeptide thiocoraline and used in SMDD. The cargo activity is ascertained via monitori...

In this work, we characterize physical hydrogels based on poly(vinyl alcohol), PVA, as intelligent biointerfaces for surface-mediated drug delivery. Specifically, we assemble microstructured (μS) surface adhered hydrogels via noncryogenic gelation of PVA, namely polymer coagulation using sodium sulfate (Na(2)SO(4)). We present systematic investigation of concentrations of Na(2)SO(4) as a tool of control over assembly of μS PVA hydrogels and quantify polymer losses and retention within the hydrogels. For polymer quantification, we use custom-made PVA with single terminal thiol group in a form of mixed disulfide with Ellman's reagent which provides for a facile UV-vis assay of polymer content in coagulation baths, subsequent washes in physiological buffer, and within the hydrogel phase. Polymer coagulation using varied concentrations of sodium sulfate afforded biointerfaces with controlled elasticity for potential uses in investigating mechano-sensitive effects of mammalian cell culture. For surface mediated drug delivery, we propose a novel concept termed Substrate Mediated Enzyme Prodrug Therapy (SMEPT) and characterize μS PVA hydrogels as reservoirs for enzymatic cargo. Assembled functional interfaces are used as matrices for cell culture and delivery of anticancer drug achieved through administration of a benign prodrug, its conversion into an active therapeutic within the hydrogel phase, and subsequent internalization by adhered hepatic cells. Taken together, the presented data contribute significantly to the development of novel matrices for surface-mediated drug delivery and other biomedical applications.