A multi-organ chip with matured tissue niches linked by vascular flow.

Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.

Emerging Trajectories for Next Generation Tissue Engineers.

The field of tissue engineering has evolved from its early days of engineering tissue substitutes to current efforts at building human tissues for regenerative medicine and mechanistic studies of tissue disease, injury, and regeneration. Advances in bioengineering, material science, and stem cell biology have enabled major developments in the field. In this perspective, we reflect on the September 2021 virtual Next Generation Tissue Engineering symposium and trainee workshop, as well as our projections for the field over the next 15 years.

Tissue-Engineered Bone Tumor as a Reproducible Human in Vitro Model for Studies of Anticancer Drugs.

Studies of anticancer therapies in traditional cell culture models can demonstrate efficacy of direct-acting compounds but lack the 3-dimensional arrangement of the tumor cells and their tissue-specific microenvironments, both of which are important modulators of treatment effects in vivo. Bone cells reside in complex environments that regulate their fate and function. A bioengineered human bone-tumor model has been shown to provide a microphysiological niche for studies of cancer cell behavior. Here, we demonstrate successful transfer between 2 laboratories and utility of this model in efficacy studies using well-established chemotherapeutic agents. The bioengineered human bone-tumor model consisted of Ewing sarcoma (RD-ES) cancer cell aggregates infused into tissue-engineered bone that was grown from human mesenchymal stem cell-derived differentiated into osteoblasts within mineralized bone scaffolds. The tumor model was maintained in culture for over 5 weeks and subjected to clinically relevant doses of linsitinib, doxorubicin, cisplatin, methotrexate, vincristine, dexamethasone, or MAP (methotrexate, doxorubicin, and cisplatin combination). Drug administration cycles were designed to mimic clinical treatment regimens. The bioengineered tumors were evaluated days to weeks after the cessation of treatment to monitor the potential for relapse, using bioengineered bone and ES cell monolayers as controls. Drug binding to the scaffolds and media proteins and gene expression were also evaluated. We show that a bioengineered human bone tumor can be used as a microphysiological model for preclinical studies of anticancer drugs. We found that anticancer efficacy was achieved at concentrations approximating the human Cmax, in contrast to traditional ES cell monolayers. These studies show that the bone-tumor model can be successfully transferred between laboratories and has predictive power in preclinical studies. The effects of drugs on the bone tumors and healthy bone were studied in parallel, in support of the utility of this model for identification of new therapeutic targets.

Regeneration of severely damaged lungs using an interventional cross-circulation platform.

The number of available donor organs limits lung transplantation, the only lifesaving therapy for the increasing population of patients with end-stage lung disease. A prevalent etiology of injury that renders lungs unacceptable for transplantation is gastric aspiration, a deleterious insult to the pulmonary epithelium. Currently, severely damaged donor lungs cannot be salvaged with existing devices or methods. Here we report the regeneration of severely damaged lungs repaired to meet transplantation criteria by utilizing an interventional cross-circulation platform in a clinically relevant swine model of gastric aspiration injury. Enabled by cross-circulation with a living swine, prolonged extracorporeal support of damaged lungs results in significant improvements in lung function, cellular regeneration, and the development of diagnostic tools for non-invasive organ evaluation and repair. We therefore propose that the use of an interventional cross-circulation platform could enable recovery of otherwise unsalvageable lungs and thus expand the donor organ pool.