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NASA NTRS2011

Principles, Techniques, and Applications of Tissue Microfluidics

The principle of tissue microfluidics and its resultant techniques has been applied to cell analysis. Building microfluidics to suit a particular tissue sample would allow the rapid, reliable, inexpensive, highly parallelized, selective extraction of chosen regions of tissue for purposes of further biochemical analysis. Furthermore, the applicability of the techniques ranges beyond the described pathology application. For example, they would also allow the posing and successful answering of new sets of questions in many areas of fundamental research. The proposed integration of microfluidic techniques and tissue slice samples is called tissue microfluidics because it molds the microfluidic architectures in accordance with each particular structure of each specific tissue sample. Thus, microfluidics can be built around the tissues, following the tissue structure, or alternatively, the microfluidics can be adapted to the specific geometry of particular tissues. By contrast, the traditional approach is that microfluidic devices are structured in accordance with engineering considerations, while the biological components in applied devices are forced to comply with these engineering presets. The proposed principles represent a paradigm shift in microfluidic technology in three important ways: Microfluidic devices are to be directly integrated with, onto, or around tissue samples, in contrast to the conventional method of off-chip sample extraction followed by sample insertion in microfluidic devices. Architectural and operational principles of microfluidic devices are to be subordinated to suit specific tissue structure and needs, in contrast to the conventional method of building devices according to fluidic function alone and without regard to tissue structure. Sample acquisition from tissue is to be performed on-chip and is to be integrated with the diagnostic measurement within the same device, in contrast to the conventional method of off-chip sample prep and subsequent insertion into a diagnostic device. A more advanced form of tissue integration with microfluidics is tissue encapsulation, wherein the sample is completely encapsulated within a microfluidic device, to allow for full surface access. The immediate applications of these approaches lie with diagnostics of tissue slices and biopsy samples e.g. for cancer but the approaches would also be very useful in comparative genomics and other areas of fundamental research involving heterogeneous tissue samples.

Wade, Lawrence A.↗

NASA NTRS2011

Principles, Techniques, and Applications of Tissue Microfluidics

Wade, Lawrence A.↗

NASA NTRS2004

Ordered Nanostructures Made Using Chaperonin Polypeptides

A recently invented method of fabricating periodic or otherwise ordered nanostructures involves the use of chaperonin polypeptides. The method is intended to serve as a potentially superior and less expensive alternative to conventional lithographic methods for use in the patterning steps of the fabrication of diverse objects characterized by features of the order of nanometers. Typical examples of such objects include arrays of quantum dots that would serve as the functional building blocks of future advanced electronic and photonic devices. A chaperonin is a double-ring protein structure having a molecular weight of about 60 plus or minus 5 kilodaltons. In nature, chaperonins are ubiquitous, essential, subcellular structures. Each natural chaperonin molecule comprises 14, 16, or 18 protein subunits, arranged as two stacked rings approximately 16 to 18 nm tall by approximately 15 to 17 nm wide, the exact dimensions depending on the biological species in which it originates. The natural role of chaperonins is unknown, but they are believed to aid in the correct folding of other proteins, by enclosing unfolded proteins and preventing nonspecific aggregation during assembly. What makes chaperonins useful for the purpose of the present method is that under the proper conditions, chaperonin rings assemble themselves into higher-order structures. This method exploits such higher-order structures to define nanoscale devices. The higher-order structures are tailored partly by choice of chemical and physical conditions for assembly and partly by using chaperonins that have been mutated. The mutations are made by established biochemical techniques. The assembly of chaperonin polypeptides into such structures as rings, tubes, filaments, and sheets (two-dimensional crystals) can be regulated chemically. Rings, tubes, and filaments of some chaperonin polypeptides can, for example, function as nano vessels if they are able to absorb, retain, protect, and release gases or chemical reagents, including reagents of medical or pharmaceutical interest. Chemical reagents can be bound in, or released from, such structures under suitable controlled conditions. In an example of a contemplated application, a two-dimensional crystal of chaperonin polypeptides would be formed on a surface of an inorganic substrate and used to form a planar array of nanoparticles or quantum dots. Through genetic engineering of the organisms used to manufacture the chaperonins, specific sites on the chaperonin molecules and, thus, on the two-dimensional crystals can be chemically modified to react in a specific manner so as to favor the deposition of the material of the desired nanoparticles or quantum dots. A mutation that introduces a cysteine residue at the desired sites on a chaperonin of Sulfolobus shibatae was used to form planar arrays of gold nanoparticles (see figure).

Trent, Jonathan↗

NASA NTRS1997

Advanced Technologies for Space Life Science Payloads on the International Space Station

SENSORS 2000! (S2K!) is a specialized, high-performance work group organized to provide advanced engineering and technology support for NASA's Life Sciences spaceflight and ground-based research and development programs. In support of these objectives, S2K! manages NASA's Advanced Technology Development Program for Biosensor and Biotelemetry Systems (ATD-B), with particular emphasis on technologies suitable for Gravitational Biology, Human Health and Performance, and Information Technology and Systems Management. A concurrent objective is to apply and transition ATD-B developed technologies to external, non-NASA humanitarian (medical, clinical, surgical, and emergency) situations and to stimulate partnering and leveraging with other government agencies, academia, and the commercial/industrial sectors. A phased long-term program has been implemented to support science disciplines and programs requiring specific biosensor (i.e., biopotential, biophysical, biochemical, and biological) measurements from humans, animals (mainly primates and rodents), and cells under controlled laboratory and simulated microgravity situations. In addition to the technology programs described above, NASA's Life and Microgravity Sciences and Applications Office has initiated a Technology Infusion process to identify and coordinate the utilization and integration of advanced technologies into its International Space Station Facilities. This project has recently identified a series of technologies, tasks, and products which, if implemented, would significantly increase the science return, decrease costs, and provide improved technological capability. This presentation will review the programs described above and discuss opportunities for collaboration, leveraging, and partnering with NASA.

Hines, John W.↗

NASA NTRS2012

Apparatus and methods for manipulation and optimization of biological systems

The invention provides systems and methods for manipulating, e.g., optimizing and controlling, biological systems, e.g., for eliciting a more desired biological response of biological sample, such as a tissue, organ, and/or a cell. In one aspect, systems and methods of the invention operate by efficiently searching through a large parametric space of stimuli and system parameters to manipulate, control, and optimize the response of biological samples sustained in the system, e.g., a bioreactor. In alternative aspects, systems include a device for sustaining cells or tissue samples, one or more actuators for stimulating the samples via biochemical, electromagnetic, thermal, mechanical, and/or optical stimulation, one or more sensors for measuring a biological response signal of the samples resulting from the stimulation of the sample. In one aspect, the systems and methods of the invention use at least one optimization algorithm to modify the actuator's control inputs for stimulation, responsive to the sensor's output of response signals. The compositions and methods of the invention can be used, e.g., to for systems optimization of any biological manufacturing or experimental system, e.g., bioreactors for proteins, e.g., therapeutic proteins, polypeptides or peptides for vaccines, and the like, small molecules (e.g., antibiotics), polysaccharides, lipids, and the like. Another use of the apparatus and methods includes combination drug therapy, e.g. optimal drug cocktail, directed cell proliferations and differentiations, e.g. in tissue engineering, e.g. neural progenitor cells differentiation, and discovery of key parameters in complex biological systems.

Ho, Chih-Ming↗

NASA NTRS1999

Stoichiometry of the large conductance bacterial mechanosensitive channel of E. coli. A biochemical study

MscL, a 15 kDa transmembrane protein, is the only component involved in the formation of a 3 nS channel in the inner membrane of Escherichia coli that opens in response to mechanical or osmotic stress. While previous data had suggested that the functional MscL complex might be a hexamer, a recent crystallographic study of the MscL homologue from M. tuberculosis reveals a pentameric structure. The present work further examines the stoichiometry of the E. coli MscL using a variety of biochemical approaches. Detergent-purified 6His-MscL in solution and MscL in the membrane could be chemically crosslinked with the products displaying ladderlike patterns on SDS gels. Three crosslinking agents (EDC, DMS, and DMA) used at saturating concentrations invariably generated pentamers as the largest product. DSS produced additional bands corresponding to larger complexes although the pentamer band appeared to be the predominant product at high levels of crosslinker. It is not clear whether these extra bands reflect a difference in the crosslinking chemistry of DSS or whether its spacer arm is the longest of those used, or a combination of both facts. For the detergent-solubilized 6His-MscL both sedimentation equilibrium and gel chromatography showed the presence of multiple species. Thus the longer spacer arm could permit both intra- and intercomplex linkages. Nonetheless, the patterns obtained with all agents are consistent with and strongly suggest a pentameric organization for the MscL channel. Expression of MscL as genetically engineered double or triple subunit tandems yields low numbers of functional channels as compared to expressed monomers. The double-tandem assemblies must have an even number of subunits and crosslinking in the membrane confirmed hexamerization. Gel chromatography clearly demonstrated that the channels formed from the double tandems were larger than those formed from WT MscL, consistent with the native channel being pentameric. The observation that both double and triple tandems form channels of normal conductance implies that the pentameric assembly is to some degree independent of the number of subunit repeats in the polypeptide precursor. The channel is thus a pentameric core with the 'extra' subunits left out of the functional complex. From sedimentation equilibrium and size-exclusion chromatography, we also conclude that MscL complexes are not in a dynamic equilibrium with monomers, but are pre-assembled; and thus, their gating properties must result from changes in the conformation of the entire complex induced by the mechanical stress.

NASA Discipline Cell Biology↗

NASA NTRS2007

The Lunar Environment: Determining the Health Effects of Exposure to Moon Dusts

The Earth s moon presents a hostile environment in which to live and work. There is no atmosphere to protect its surface from the ravages of solar wind and micrometeorite impacts. As a result, the moon s surface is covered with a thin layer of fine, charged, reactive dust capable of entering habitats and vehicle compartments, where it can result in crewmember health problems. During the Apollo missions, lunar dusts were introduced into the crew vehicle, resulting in direct exposure and occasional reports of respiratory, dermal and ocular irritation. In order to study the toxicological effects of lunar dust, NASA formed the Lunar Airborne Dust Toxicity Advisory Group (LADTAG). This interdisciplinary group is comprised of leading experts in space toxicology, lunar geology, space medicine and biomedical research. LADTAG has demonstrated that lunar soil contains several types of reactive dusts, including an extremely fine respirable component. These dusts have highly reactive surfaces in the lunar environment; the grains contain surface coatings which are generated by vapor phases formed by hypervelocity impact of micrometeorites. This unique class of dusts has surface properties that are unlike any Earth based analog. These distinctive properties are why lunar dusts are of great toxicological interest. Understanding how these reactive components behave "biochemically" in a moisture-rich pulmonary environment will aid in determining how toxic these particles are to humans. The data obtained from toxicological examination of lunar dusts will determine the human risk criteria for lunar dust exposure and produce a lunar health standard. LADTAG s analysis of lunar dusts and lunar dust simulants will include detailed lunar particle characterizations, determining the properties of particle activation, reactivation of lunar dust, the process of dust passivation and discerning the pathology of lunar dust exposure via inhalation, intratracheal instillation, cell culture exposure, dermal exposure and ocular exposure. The resulting health standard will be time-based and will vary by the duration and type of exposure. It may also be necessary to set multiple standards for different types of lunar dust, as well as for dust in its activated form vs. aged & passivated dust. This standard, set to protect the health of our robust astronaut crews, will not only impact NASA medical operations, but engineering designs as well. The data from our multidisciplinary research are vital in developing remediation devices and environmental monitors. Ultimately, the engineering and safety groups will design and develop countermeasures for space vehicles, suits, rovers and habitats that will be sustained within the limits of the health standard.

Khan-Mayberry, Noreen↗

NASA NTRS2002

Trends in lignin modification: a comprehensive analysis of the effects of genetic manipulations/mutations on lignification and vascular integrity

A comprehensive assessment of lignin configuration in transgenic and mutant plants is long overdue. This review thus undertook the systematic analysis of trends manifested through genetic and mutational manipulations of the various steps associated with monolignol biosynthesis; this included consideration of the downstream effects on organized lignin assembly in the various cell types, on vascular function/integrity, and on plant growth and development. As previously noted for dirigent protein (homologs), distinct and sophisticated monolignol forming metabolic networks were operative in various cell types, tissues and organs, and form the cell-specific guaiacyl (G) and guaiacyl-syringyl (G-S) enriched lignin biopolymers, respectively. Regardless of cell type undergoing lignification, carbon allocation to the different monolignol pools is apparently determined by a combination of phenylalanine availability and cinnamate-4-hydroxylase/"p-coumarate-3-hydroxylase" (C4H/C3H) activities, as revealed by transcriptional and metabolic profiling. Downregulation of either phenylalanine ammonia lyase or cinnamate-4-hydroxylase thus predictably results in reduced lignin levels and impaired vascular integrity, as well as affecting related (phenylpropanoid-dependent) metabolism. Depletion of C3H activity also results in reduced lignin deposition, albeit with the latter being derived only from hydroxyphenyl (H) units, due to both the guaiacyl (G) and syringyl (S) pathways being blocked. Apparently the cells affected are unable to compensate for reduced G/S levels by increasing the amounts of H-components. The downstream metabolic networks for G-lignin enriched formation in both angiosperms and gymnosperms utilize specific cinnamoyl CoA O-methyltransferase (CCOMT), 4-coumarate:CoA ligase (4CL), cinnamoyl CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD) isoforms: however, these steps neither affect carbon allocation nor H/G designations, this being determined by C4H/C3H activities. Such enzymes thus fulfill subsidiary processing roles, with all (except CCOMT) apparently being bifunctional for both H and G substrates. Their severe downregulation does, however, predictably result in impaired monolignol biosynthesis, reduced lignin deposition/vascular integrity, (upstream) metabolite build-up and/or shunt pathway metabolism. There was no evidence for an alternative acid/ester O-methyltransferase (AEOMT) being involved in lignin biosynthesis.The G/S lignin pathway networks are operative in specific cell types in angiosperms and employ two additional biosynthetic steps to afford the corresponding S components, i.e. through introduction of an hydroxyl group at C-5 and its subsequent O-methylation. [These enzymes were originally classified as ferulate-5-hydroxylase (F5H) and caffeate O-methyltransferase (COMT), respectively.] As before, neither step has apparently any role in carbon allocation to the pathway; hence their individual downregulation/manipulation, respectively, gives either a G enriched lignin or formation of the well-known S-deficient bm3 "lignin" mutant, with cell walls of impaired vascular integrity. In the latter case, COMT downregulation/mutation apparently results in utilization of the isoelectronic 5-hydroxyconiferyl alcohol species albeit in an unsuccessful attempt to form G-S lignin proper. However, there is apparently no effect on overall G content, thereby indicating that deposition of both G and S moieties in the G/S lignin forming cells are kept spatially, and presumably temporally, fully separate. Downregulation/mutation of further downstream steps in the G/S network [i.e. utilizing 4CL, CCR and CAD isoforms] gives predictable effects in terms of their subsidiary processing roles: while severe downregulation of 4CL gave phenotypes with impaired vascular integrity due to reduced monolignol supply, there was no evidence in support of increased growth and/or enhanced cellulose biosynthesis. CCR and CAD downregulation/mutations also established that a depletion in monolignol supply reduced both lignin contents supply reduced both lignin contents and vascular integrity, with a concomitant shift towards (upstream) metabolite build-up and/or shunting.The extraordinary claims of involvement of surrogate monomers (2-methoxybenzaldehyde, feruloyl tyramine, vanillic acid, etc.) in lignification were fully disproven and put to rest, with the investigators themselves having largely retracted former claims. Furthermore analysis of the well-known bm1 mutation, a presumed CAD disrupted system, apparently revealed that both G and S lignin components were reduced. This seems to imply that there is no monolignol specific dehydrogenase, such as the recently described sinapyl alcohol dehydrogenase (SAD) for sinapyl alcohol formation. Nevertheless, different CAD isoforms of differing homology seem to be operative in different lignifying cell types, thereby giving the G-enriched and G/S-enriched lignin biopolymers, respectively. For the G-lignin forming network, however, the CAD isoform is apparently catalytically less efficient with all three monolignols than that additionally associated with the corresponding G/S lignin forming network(s), which can more efficiently use all three monolignols. However, since CAD does not determine either H, G, or S designation, it again serves in a subsidiary role-albeit using different isoforms for different cell wall developmental and cell wall type responses.The results from this analysis contrasts further with speculations of some early investigators, who had viewed lignin assembly as resulting from non-specific oxidative coupling of monolignols and subsequent random polymerization. At that time, though, the study of the complex biological (biochemical) process of lignin assembly had begun without any of the (bio)chemical tools to either address or answer the questions posed as to how its formation might actually occur. Today, by contrast, there is growing recognition of both sophisticated and differential control of monolignol biosynthetic networks in different cell types, which serve to underscore the fact that complexity of assembly need not be confused any further with random formation. Moreover, this analysis revealed another factor which continues to cloud interpretations of lignin downregulation/mutational analyses, namely the serious technical problems associated with all aspects of lignin characterization, whether for lignin quantification, isolation of lignin-enriched preparations and/or in determining monomeric compositions. For example, in the latter analyses, some 50-90% of the lignin components still cannot be detected using current methodologies, e.g. by thioacidolysis cleavage and nitrobenzene oxidative cleavage. This deficiency in lignin characterization thus represents one of the major hurdles remaining in delineating how lignin assembly (in distinct cell types) and their configuration actually occurs.

Review, Academic↗