Macrocyclization of enzyme-based supramolecular polymers

AB type monomers for supramolecular polymers have been developed based on the strong and reversible noncovalent interaction between ribonuclease S-peptide (A) and S-protein (B), resulting in an active enzyme complex as the linking unit. Two AB-type protein constructs are synthesized differing in the length of the flexible oligo(ethylene glycol) spacer separating the two end groups. Using an experimental setup where size exclusion chromatography is directly coupled to Q-TOF mass spectrometry, we have analyzed the self-assembled architectures as a function of concentration. The theory of macrocyclization under thermodynamic control is used to quantitatively analyze the experimental data. Using this theory, we show that AB-type monomers linked by flexible linkers grow reversibly via ring-chain competition. Inherently the formation of linear polymeric assemblies is beyond the capability of these types of building blocks due to concentration limits of proteins. The results therefore contribute to the general understanding of supramolecular polymerization with biological building blocks and demonstrate design requirements for monomers if linear polymerization is desired

Sustained Delivery of Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Stimulates Endogenous Cardiac Repair in the Chronic Infarcted Pig Heart

Activation of endogenous cardiac stem/progenitor cells (eCSCs) can improve cardiac repair after acute myocardial infarction. We studied whether the in situ activation of eCSCs by insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) could be increased using a newly developed hydrogel in chronic myocardial infarction (MI). One-month post-MI pigs underwent NOGA-guided intramyocardial injections of IGF-1/HGF (GF: both 0.5 μg/mL, n = 5) or IGF-1/HGF incorporated in UPy hydrogel (UPy-GF; both 0.5 μg/mL, n = 5). UPy hydrogel without added growth factors was administered to four control (CTRL) pigs. Left ventricular ejection fraction was increased in the UPy-GF and GF animals compared to CTRLs. UPy-GF delivery reduced pathological hypertrophy, led to the formation of new, small cardiomyocytes, and increased capillarization. The eCSC population was increased almost fourfold in the border zone of the UPy-GF-treated hearts compared to CTRL hearts. These results show that IGF-1/HGF therapy led to an improved cardiac function in chronic MI and that effect size could be further increased by using UPy hydrogel. Electronic supplementary material The online version of this article (doi:10.1007/s12265-013-9518-4) contains supplementary material, which is available to authorized users

A Fast pH-Switchable and Self-Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium

Minimally invasive intervention strategies after myocardial infarction use state-of-the-art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH-switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1-m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self-healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model

Programmable Control in Extracellular Matrix-mimicking Polymer Hydrogels

The extracellular matrix (ECM) and cells have a reciprocal relationship, one shapes the other and vice versa. One of the main challenges of synthetic material systems for developmental cell culturing, organoid and stem cell work includes the implementation of this reciprocal nature. The largest hurdle to achieve true cell-instructive materials in biomaterials engineering is a lack of spatial and temporal control over material properties and the display of bioactive signals compared to the natural cell environment. ECM-mimicking hydrogels have been developed using a wide range of polymers, assembly and cross-linking strategies. While our synthetic toolbox is larger than nature, often our systems underperform when compared to ECM systems with natural components like Matrigel. Material properties and three-dimensional structure ill-represent the three-dimensional ECM reciprocal nature and ligand presentation is an oversimplified version of the complexity found in nature. We hypothesize that the lack of programmable control in properties and ligand presentation forms the basis of this mismatch in performance and analyze the presence of control in current state of the art ECM-mimicking systems based on covalent, supramolecular and recombinant polymers. We conclude that through combining the dynamics of supramolecular materials, robustness from covalent systems and the programmable spatial control of bio-activation in recombinant ECM materials, the optimal synthetic artificial ECM could be assembled

Nucleic acids presenting polymer nanomaterials as vaccine adjuvants

Most vaccines developed today include only the antigens that best stimulate the immune system rather than the entire virus or microbe, which makes vaccine production and use safer and easier, though they lack potency to induce acceptable immunity and long-term protection. The incorporation of additional immune stimulating components, named adjuvants, is required to generate a strong protective immune response. Nucleic acids (DNA and RNA) and their synthetic analogs are promising candidates as vaccine adjuvants activating Toll-like receptors (TLRs). Additionally, in the last few years several nanocarriers have emerged as platforms for targeted co-delivery of antigens and adjuvants. In this review, we focus on the recent developments in polymer nanomaterials presenting nucleic acids as vaccine adjuvants. We aim to compare the effectiveness of the various classes of polymers in immune modulating materials (nanoparticles, dendrimers, single-chain particles, nanogels, polymersomes and DNA-based architectures). In particular, we address the critical role of parameters such as size, shape, complexation and release of TLR ligands, cellular uptake, stability, toxicity and potential importance of spatial control in ligand presentation