The Tin Man Needs a Heart: A Proposed Framework for the Regulation of Bioprinted Organs

Each day, seventeen people die in the United States while waiting for an organ transplant. At least part of this need could be met by bioprinting, a technology that allows the on-demand production of custom-sized organs from a patient’s own cells. The field of bioprinting is progressing rapidly: the first bioprinted organs have already entered the clinic. Yet, developers of bioprinted organs face significant uncertainty as to how their potentially lifesaving products will be regulated—and by which government agency. Such regulatory uncertainty has the potential to decrease investment and stifle innovation in this promising technological field. This Note examines how the current framework for the regulation of medical products and human organs might be applied to bioprinted organs. This Note concludes that the existing regulatory schemes do not sufficiently address the specific regulatory needs created by bioprinted organs, which are uniquely interdisciplinary materials. Therefore, this Note proposes a new regulatory framework to reduce uncertainty for bioprinted organ developers and to promote patient access to these bioprinted materials that might soon serve as safe and effective replacements for donor organs

Genetic Selection for Enhanced Folding In Vivo Targets the Cys14-Cys38 Disulfide Bond in Bovine Pancreatic Trypsin Inhibitor

The periplasm provides a strongly oxidizing environment; however, periplasmic expression of proteins with disulfide bonds is often inefficient. Here, we used two different tripartite fusion systems to perform in vivo selections for mutants of the model protein bovine pancreatic trypsin inhibitor (BPTI) with the aim of enhancing its expression in Escherichia coli. This trypsin inhibitor contains three disulfides that contribute to its extreme stability and protease resistance. The mutants we isolated for increased expression appear to act by eliminating or destabilizing the Cys14-Cys38 disulfide in BPTI. In doing so, they are expected to reduce or eliminate kinetic traps that exist within the well characterized in vitro folding pathway of BPTI. These results suggest that elimination or destabilization of a disulfide bond whose formation is problematic in vitro can enhance in vivo protein folding. The use of these in vivo selections may prove a valuable way to identify and eliminate disulfides and other rate-limiting steps in the folding of proteins, including those proteins whose in vitro folding pathways are unknown. Antioxid. Redox Signal. 14, 973-984.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90494/1/ars-2E2010-2E3712.pd

The Tin Man Needs a Heart: A Proposed Framework for the Regulation of Bioprinted Organs

Each day, seventeen people die in the United States while waiting for an organ transplant. At least part of this need could be met by bioprinting, a technology that allows the on-demand production of custom-sized organs from a patient’s own cells. The field of bioprinting is progressing rapidly: the first bioprinted organs have already entered the clinic. Yet, developers of bioprinted organs face significant uncertainty as to how their potentially lifesaving products will be regulated—and by which government agency. Such regulatory uncertainty has the potential to decrease investment and stifle innovation in this promising technological field. This Note examines how the current framework for the regulation of medical products and human organs might be applied to bioprinted organs. This Note concludes that the existing regulatory schemes do not sufficiently address the specific regulatory needs created by bioprinted organs, which are uniquely interdisciplinary materials. Therefore, this Note proposes a new regulatory framework to reduce uncertainty for bioprinted organ developers and to promote patient access to these bioprinted materials that might soon serve as safe and effective replacements for donor organs

Biomimetic lipid nanoparticles as treatment for bacterial sepsis (HUM4P.275)

Abstract Sepsis describes a spectrum of potentially fatal medical conditions caused by the inflammatory response of the human body to an infectious insult. Due to significant morbidity and high mortality, new treatments are urgently needed specifically targeting the cause of sepsis. Gram-negative sepsis is elicited by lipopolysaccharides (LPS). Recognition of these bacterial cell wall components by TLR4 and accessory proteins leads to activation of complement and coagulation systems and the release of pro-inflammatory agents. Human high-density lipoproteins (hHDL) can bind LPS and reduce its levels in the blood. However, remodeling and depletion of HDL during sepsis impairs HDLs’ immune-protective capacity. Thus, we sought to design nanoparticles (NP) that mimic hHDL in shape and surface chemistry, yet exceeded its LPS-binding properties and boosted LPS detoxification. Convincingly, our data show that HDL-like NPs effectively reduce the LPS-induced production of cytokines in human monocytic cell lines and in whole human blood. Our NPs, but not hHDL, exert their immune-protective function at low nM concentrations when stimulated with LPS concentrations above those levels reported in sepsis patients. Further, our NPs are non-immunogenic and non-toxic to target cells. As such, our NPs have the great potential for an LPS antidote that rapidly detoxifies LPS in the blood, drastically inhibits the release of inflammatory mediators, and constitutes a highly effective treatment for sepsis.</jats:p