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Current cell-culture is largely performed on synthetic two-dimensional (2D) petri dishes or permeable supports such as Boyden chambers, mostly because of their ease of use and established protocols. It is generally accepted that modern cell biology research requires new physiologically relevant three-dimensional (3D) cell culture platform to mimic in vivo cell responses. To that end, we report the design and development of a suspended hydrogel membrane (ShyM) platform using gelatin methacrylate (GelMA) hydrogel. ShyM thickness (0.25–1 mm) and mechanical properties (10–70 kPa) can be varied by controlling the size of the supporting grid and concentration of GelMA prepolymer, respectively. GelMA ShyMs, with dual media exposure, were found to be compatible with both the cell-seeding and the cell-encapsulation approach as tested using murine 10T1/2 cells and demonstrated higher cellular spreading and proliferation as compared to flat GelMA unsuspended control. The utility of ShyM was also demonstrated using a case-study of invasion of cancer cells. ShyMs, similar to Boyden chambers, are compatible with standard well-plates designs and can be printed using commonly available 3D printers. In the future, ShyM can be potentially extended to variety of photosensitive hydrogels and cell types, to develop new in vitro assays to investigate complex cell–cell and cell–extracellular matrix (ECM) interactions.

Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(D,L-lactide) (PEG-PLA) micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.