Thiol-ene and photo-cleavage chemistry for controlled presentation of biomolecules in hydrogels

Abstract

Hydrogels have emerged as promising scaffolds in regenerative medicine for the delivery of biomolecules to promote healing. However, increasing evidence suggests that the context that biomolecules are presented to cells (e.g., as soluble verses tethered signals) can influence their bioactivity. A common approach to deliver biomolecules in hydrogels involves physically entrapping them within the network, such that they diffuse out over time to the surrounding tissues. While simple and versatile, the release profiles in such system are highly dependent on the molecular weight of the entrapped molecule relative to the network structure, and it can be difficult to control the release of two different signals at independent rates. In some cases, supraphysiologically high loadings are used to achieve therapeutic local concentrations, but uncontrolled release can then cause deleterious off-target side effects. In vivo, many growth factors and cytokines are stored in the extracellular matrix (ECM) and released on demand as needed during development, growth, and wound healing. Thus, emerging strategies in biomaterial chemistry have focused on ways to tether or sequester biological signals and engineer these bioactive scaffolds to signal to delivered cells or endogenous cells. While many strategies exist to achieve tethering of peptides, protein, and small molecules, this review focuses on photochemical methods, and their usefulness as a mild reaction that proceeds with fast kinetics in aqueous solutions and at physiological conditions. Photo-click and photo-caging methods are particularly useful because one can direct light to specific regions of the hydrogel to achieve spatial patterning. Recent methods have even demonstrated reversible introduction of biomolecules to mimic the dynamic changes of native ECM, enabling researchers to explore how the spatial and dynamic context of biomolecular signals influences important cell functions. This review will highlight how two photochemical methods have led to important advances in the tissue regeneration community, namely the thiol-ene photo-click reaction for bioconjugation and photocleavage reactions that allow for the removal of protecting groups. Specific examples will be highlighted where these methodologies have been used to engineer hydrogels that control and direct cell function with the aim of inspiring their use in regenerative medicine.

Rapid Bioorthogonal Chemistry Turn-on through Enzymatic or Long Wavelength Photocatalytic Activation of Tetrazine Ligation

“…In particular, photoinducible reactions have emerged as a method for turning on bioorthogonal reactions with temporal and spatial control. 9,16 Key advances include tetrazole 10 and cyclopropenone 11 based ligations, where photolysis produces reactive nitrile imines and cyclooctyne derivatives, respectively. Such ‘photoclick’ reactions generally utilize short-wavelength light to unleash more reactive species.…”

Thiol‐ene Hydrogels for Local Delivery of PTH for Bone Regeneration in Critical Size defects

“…It is presently unknown whether diffusion would occur more slowly in a much larger hydrogel or if the release profile would be similar. The rapid release observed in these hydrogels is likely due to the small size of PTH in comparison with the mesh size of the hydrogel . Notably, in this study, the released PTH measures for days 21 and 28 have somewhat higher variance and some values indicating slightly more than 100% release.…”

Covalent modification of biological targets with natural products through Paal–Knorr pyrrole formation

“…Akin to reaction design, the chemical biologist is now experiencing the advance of tools like the Staudinger ligation 3 or Huisgen-based click chemistry, 4 which can be modulated to fit one’s exact biological needs. The same is true for other types of facile chemical processes such as thiol–ene, 5 Diels–Alder, 6 or photo-click chemistry. 7 These reactions have played a fundamental role in bridging the gap between chemical and biological studies.…”