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Photocrosslinked hydrogels, such as methacrylate-modified gelatin (gelMA) and hyaluronic acid (HAMA), are widely utilized as tissue engineering scaffolds and/or drug delivery vehicles, but lack a suitable means for non-invasive, longitudinal monitoring of surgical placement, biodegradation, and drug release. Therefore, we developed a novel photopolymerizable X-ray contrast agent, methacrylate-modified gold nanoparticles (AuMA NPs), to enable covalent-linking to methacrylate-modified hydrogels (gelMA and HAMA) in one-step during photocrosslinking and non-invasive monitoring by X-ray micro-computed tomography (micro-CT). Hydrogels exhibited a linear increase in X-ray attenuation with increased Au NP concentration to enable quantitative imaging by contrast-enhanced micro-CT. The enzymatic and hydrolytic degradation kinetics of gelMA-Au NP hydrogels were longitudinally monitored by micro-CT for up to one month in vitro, yielding results that were consistent with concurrent measurements by optical spectroscopy and gravimetric analysis. Importantly, AuMA NPs did not disrupt the hydrogel network, rheology, mechanical properties, and hydrolytic stability compared with gelMA alone. GelMA-Au NP hydrogels were thus able to be bioprinted into well-defined three-dimensional architectures supporting endothelial cell viability and growth. Overall, AuMA NPs enabled the preparation of both conventional photopolymerized hydrogels and bioprinted scaffolds with tunable X-ray contrast for noninvasive, longitudinal monitoring of placement, degradation, and NP release by micro-CT.

Tissue engineering is a rapidly evolving, multidisciplinary field that aims at generating or regenerating 3D functional tissues for in vitro disease modeling and drug screening applications or for in vivo therapies. A variety of advanced biological and engineering methods are increasingly being used to further enhance and customize the functionality of tissue engineered scaffolds. To this end, tunable drug delivery and release mechanisms are incorporated into tissue engineering modalities to promote different therapeutic processes, thus, addressing challenges faced in the clinical applications. In this review, we elaborate the mechanisms and recent developments in different drug delivery vehicles, including the quantum dots, nano/micro particles, and molecular agents. Different loading strategies to incorporate the therapeutic reagents into the scaffolding structures are explored. Further, we discuss the main mechanisms to tune and monitor/quantify the release kinetics of embedded drugs from engineered scaffolds. We also survey the current trend of drug delivery using stimuli driven biopolymer scaffolds to enable precise spatiotemporal control of the release behavior. Recent advancements, challenges facing current scaffold-based drug delivery approaches, and areas of future research are discussed.

Biodegradable materials, such as collagen scaffolds, are used extensively in clinical medicine for tissue regeneration and/or as an implantable drug delivery vehicle. However, available methods to study biomaterial degradation are typically invasive, destructive, and/or non-volumetric. Therefore, the objective of this study was to investigate a new method for nondestructive, longitudinal, and volumetric measurement of collagen scaffold degradation. Gold nanoparticles (Au NPs) were covalently conjugated to collagen fibrils during scaffold preparation to enable contrast-enhanced imaging of collagen scaffolds. The X-ray attenuation of as-prepared scaffolds increased linearly with increased Au NP concentration such that ≥60 mM Au NPs provided sufficient contrast to measure scaffold degradation. Collagen scaffold degradation kinetics were measured to increase during in vitro enzymatic degradation in media with an increased concentration of collagenase. The scaffold degradation kinetics measured by micro-CT exhibited lower variability compared with gravimetric measurement and were validated by measurement of the release of Au NPs from the same samples by optical spectroscopy. Thus, Au NPs and CT synergistically enabled nondestructive, longitudinal, and volumetric measurement of collagen scaffold degradation.