Spatiotemporal material functionalization via competitive supramolecular complexation of avidin and biotin analogs (original) (raw)
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Here we describe methods for synthesizing a cationic, multi-arm Avidin (mAv) nano-construct that has a wide range of applications in drug delivery and imaging of negatively charged tissues. We use Avidin-biotin technology that gives the flexibility for conjugating biotinylated Dexamethasone to mAv by simple mixing at room temperature. We also describe methods to control hydrolysis rates of ester linkers to enable sustained (and tunable) drug release rates in therapeutic doses. •Multi-arm structure provides multiple sites for covalent conjugation of drugs •Use of Avidin-biotin reaction gives multi-arm nano-construct a modular design enabling conjugation and delivery of similar sized biotinylated drugs.
Spatially and temporally controlled hydrogels for tissue engineering
Recent years have seen tremendous advances in the field of hydrogel-based biomaterials. One of the most prominent revolutions in this field has been the integration of elements or techniques that enable spatial and temporal control over hydrogels' properties and functions. Here, we critically review the emerging progress of spatiotemporal control over biomaterial properties towards the development of functional engineered tissue constructs. Specifically, we will highlight the main advances in the spatial control of biomaterials, such as surface modification, microfabrication, photo-patterning, and bioprinting, as well as advances in the temporal control of biomaterials, such as controlled release of molecules, photocleaving of proteins, and controlled hydrogel degradation. We believe that the development and integration of these techniques will drive the evolution of next-generation engineered tissues.
ACS Central Science, 2018
Biomolecule-functionalized hydrogels have emerged as valuable cell culture platforms to recapitulate the mechanical and biochemical properties of the extracellular niche. The typical strategy to functionalize hydrogels with biomolecules involves directly tethering them to the hydrogel backbone resulting in a static material. Thus, this approach fails to capture the dynamic changes in biomolecule composition that occur during biological processes or that may be required for regenerative medicine applications. Moreover, it also limits the scope of biomolecules to simple peptides, as signaling proteins generally have poor stability under cell culture conditions and lose their bioactivity over time. To that end, we sought to develop a bioconjugation reaction that would enable reversible and repeatable tethering of signaling proteins to hydrogels, so that spent protein could be released on-demand and replaced with fresh protein as needed. Specifically, we designed an allyl sulfide chaintransfer agent that enables a reversible, photomediated, thiol−ene bioconjugation of signaling proteins to hydrogels. Upon addition of a thiolated protein to the allyl sulfide moiety, the previously tethered protein is released, and the "ene" functionality is regenerated. Using this approach, we demonstrate that protein patterning can be achieved in hydrogels through a thiol−ene reaction, and the patterned protein can then be released through a subsequent thiol−ene reaction of a PEG thiol. Importantly, this process is repeatable through multiple iterations and proceeds at physiologically relevant signaling protein concentrations. Finally, we demonstrate that whole signaling proteins can be patterned and released in the presence of cells, and that cells respond to their presentation with spatial fidelity. Combined, these data represent the first example of a methodology that enables fully reversible and repeatable patterning and release of signaling proteins from hydrogels.
International Journal of Molecular Sciences
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Progress in Polymer Science, 2019
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Polymer International, 2014
Hydrogel-forming materials that mimic the three-dimensional architecture and properties of tissue are known to have a positive effect on cellular differentiation and growth. A subset of those are in situ gels, which utilise in vivo conditions like pH (e.g. acetate phthalate), temperature (e.g. poloxamer) and ionic concentration (e.g. Gelrite™), and can be used to facilitate the delivery of cells to an affected tissue. Hence, we have developed in situ hydrogels based on gellan and hydroxypropylmethylcellulose (HPMC), which are known to be triggered through ions and temperature, respectively, as matrices to deliver cells. Gellan/HPMC blends had a lower gelation temperature than gellan alone crosslinked with calcium, suggesting the role of the dual trigger. Average storage modulus at a frequency of 10 Hz for gellan crosslinked with 3 mmol L −1 calcium was 4.53 × 10 3 Pa; for 9:1 gellan/HPMC crosslinked with 3 mmol L −1 calcium was 5.59 × 10 3 Pa; and for 8:2 gellan/HPMC crosslinked with 3 mmol L −1 calcium was 2.13 × 10 3 Pa, suggesting tunable stiffness by changing the gellan-to-HPMC ratio. Hydrophilicity was confirmed using goniometry with a contact angle much less than 90 ∘ , facilitating the passage of cells and electrolytes when using the gels as scaffolds. The gels were also found to be porous and non-toxic to fibroblast cell line L929 and osteosarcoma cell line MG-63, which, when encapsulated within the gels, were able to grow and proliferate. These blended hydrogels are suitable as scaffolds to encapsulate cells, with tunable stiffness modulated by varying the concentration of gellan and HPMC.
Multicomponent self-assembly: Supramolecular design of complex hydrogels for biomedical applications
2018
Human body is an archetypal of multicomponent hydrogels, precisely fabricated by nature’s intelligent use of supramolecular self-assembly of various building blocks. Therefore, in order to regenerate impaired tissues, the use of multicomponent self-assembly is fast becoming an attractive strategy for developing bio-relevant hydrogels that recapitulate the complexity and multifunctionality of native tissues. As such, in this chapter we focus on the concept of multicomponent self-assembly as a biomimetic approach for developing hydrogel biomaterials for biomedical applications using various mixtures of building blocks of different molecular sizes (small-small molecules, small molecules-macromolecule, and macromolecules) and sources (amino acids, peptides, saccharides, and nucleobases).
Multivalency Enables Dynamic Supramolecular HostGuest Hydrogel Formation
Supramolecular and dynamic biomaterials hold promise to recapitulate the time-dependent properties and stimuli-responsiveness of the native extracellular matrix (ECM). Host−guest chemistry is one of the most widely studied supramolecular bonds, yet the binding characteristics of host−guest complexes (β-CD/adamantane) in relevant biomaterials have mostly focused on singular host−guest interactions or nondiscrete multivalent pendent polymers. The stepwise synergistic effect of multivalent host−guest interactions for the formation of dynamic biomaterials remains relatively unreported. In this work, we study how a series of multivalent adamantane (guest) cross-linkers affect the overall binding affinity and ability to form supramolecular networks with alginate-CD (Alg-CD). These binding constants of the multivalent cross-linkers were determined via NMR titrations and showed increases in binding constants occurring with multivalent constructs. The higher multivalent cross-linkers enabled hydrogel formation; furthermore, an increase in binding and gelation was observed with the inclusion of a phenyl spacer to the cross-linker. A preliminary screen shows that only cross-linking Alg-CD with an 8-arm-multivalent guest results in robust gel formation. These cytocompatible hydrogels highlight the importance of multivalent design for dynamically cross-linked hydrogels. These materials hold promise for development toward cell-and small molecule-delivery platforms and allow discrete and fine-tuning of network properties.