The successful transport of drug- and cell-based therapeutics to diseased sites represents a major barrier in the development of clinical therapies. Targeted delivery can be mediated through degradable biomaterial vehicles that utilize disease biomarkers to trigger payload release. Here, we report a modular chemical framework for imparting hydrogels with precise degradative responsiveness by using multiple environmental cues to trigger reactions that operate user-programmable Boolean logic. By specifying the molecular architecture and connectivity of orthogonal stimuli-labile moieties within material crosslinkers, we show selective control over gel dissolution and therapeutic delivery. To illustrate the versatility of this methodology, we synthesized seventeen distinct stimuli-responsive materials that collectively yielded all possible YES/OR/AND logical outputs from input combinations involving enzyme, reductant, and light. Using these hydrogels we demonstrate the first sequential and environmentally stimulated release of multiple cell lines in well-defined combinations from a material. We expect these platforms will find utility in several diverse fields including drug delivery, diagnostics, and regenerative medicine.

A photodegradable material-based approach to generate endothelialized 3D vascular networks within cell-laden hydrogel biomaterials is introduced. Exploiting multiphoton lithography, microchannel networks spanning nearly all size scales of native human vasculature are readily generated with unprecedented user-defined 4D control. Intraluminal channel architectures are fully customizable, providing new opportunities for next-generation microfluidics and directed cell function.

Stimuli-responsive materials undergo triggered changes when presented with specific environmental cues. These dynamic systems can leverage biological signals found locally within the body as well as exogenous cues administered with spatiotemporal control, providing powerful opportunities in next-generation diagnostics and personalized medicine. Here, we review the synthetic and strategic advances used to impart diverse responsiveness to a wide variety of biomaterials. Categorizing systems on the basis of material type, number of inputs, and response mechanism, we examine past and ongoing efforts toward endowing biomaterials with customizable sensitivity. We draw an analogy to computer science, whereby a stimuli-responsive biomaterial transduces a set of inputs into a functional output as governed by a user-specified logical operator. We discuss Boolean and non-Boolean operations, as well as the various chemical and physical modes of signal transduction. Finally, we examine current limitations and promising directions in the ongoing development of programmable stimuli-responsive biomaterials.

The controlled presentation of proteins from and within materials remains of significant interest for many bioengineering applications. Though "smart" platforms offer control over protein release in response to a single external cue, no strategy has been developed to trigger delivery in response to userspecified combinations of environmental inputs, nor to independently control the release of multiple species from a homogenous material. In this work, we introduce a modular semisynthetic scheme to govern the release of site-specifically modified proteins from hydrogels following Boolean logic. A sortase-mediated transpeptidation reaction was used to generate recombinant proteins C-terminally tethered to gels through environmentally sensitive degradable linkers. By varying the connectivity of multiple stimuli-labile moieties within these customizable linkers, we exhaustively demonstrate YES/OR/AND control of protein release in response to one and two-input combinations involving enzyme, reductant, and light. Tethering of multiple proteins each through a different stimuli-sensitive linker permits their independent and sequential release from a common material. We expect these methodologies to enable new opportunities in tissue engineering and therapeutic delivery.

No abstract