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Monolithically Integrated ImplantableFflexible Antenna for Electrocorticography and Related Biotelemetry Devices

A sub-skin-depth (nanoscale metallization) thin film antenna is shown that is monolithically integrated with an array of neural recording electrodes on a flexible polymer substrate. The structure is intended for long-term biometric data and power transfer such as electrocorticographic neural recording in a wireless brain-machine interface system. The system includes a microfabricated thin-film electrode array and a loop antenna patterned in the same microfabrication process, on the same or on separate conductor layers designed to be bonded to an ultra-low power ASIC.

Heterochronic Blood Exchange As A Modality To Influence Myogenesis, Neurogenesis, And Liver Regeneration

One reason for waning capabilities with advancing age is a progressive decline in organ function. Heterochronic parabiosis rejuvenates the performance of old tissues' stem cells at some expense to the young, but whether this is through shared circulatory factors or shared organ systems is unclear; and parabiosis is not a clinically adaptable approach. The old heterochronic partners have access to young organs, environmental enrichment and youthful hormones/pheromones, while the young parabiont maintains an additional aged body with deteriorating organs. In contrast to the permanent anastomosis of parabiosis, UC Berkeley researchers have used a small animal blood exchange where animals are connected and disconnected at will, removing the influence of shared organs, adaptation to being joined, etc. The effects of heterochronic blood exchange were examined with respect to all three germ layer derivatives: injured-regenerating muscle, ongoing liver cell proliferation and brain - hippocampal neurogenesis, and in the presence and absence of muscle injury.  The influence of heterochronic blood exchange on myogenesis, neurogenesis and hepatogenesis was fast, within a few days.  These findngs suggest a rapid translation of blood apheresis (FDA approved for other diseases, but not for the degenerative pathologies) for therapy to attenuate and reverse liver fibrosis and adiposity, muscle wasting and neuro-degeneration.  

Mechano-Nps (Node Pore Sensing)

The mechanical properties of cells derive from the structure and dynamics of their intracellular components, including the cytoskeleton, cell membrane, nucleus, and other organelles.  These, in turn, emerge from cell specific genetic, epigenetic, and biochemical programs, providing a link between cellular mechanics and the underlying molecular state.  Differences in mechanical properties reflect on cellular properties with clinical implications, including the metastatic potential, cell-cycle stage, and differentiation state of cells.  Yet, many mechanical aspects of various cells and sub-cell organelles remain unknown due to absence of appropriate analysis platforms. Atomic-force microscopy (AFM) and micropipette aspiration are the gold standards for performing mechanical measurements of cells, as they both provide controlled loading conditions and quantify such cellular properties as elastic modulus and cortical tension.  They are, however, burdened by slow throughput, capable of analyzing only just a few cells/hr.  Likewise, optical tweezers and microplate rheometry also suffer from low throughput.  Various microfluidic based platforms have been proposed for the high-throughput mechanical analysis of cells, including hydrodynamic stretching cytometry, suspended microchannel resonators (SMR), and real-time deformability cytometry (RT-DC).  Although each of these methods can analyze populations of cells in a relatively short time, they focus only on a single cellular property.  Consequently, these platforms, and the low-throughput traditional methods that under-sample, can neither identify cellular heterogeneity nor classify mechanical sub-phenotypes within a population. Investigators at UC Berkeley have developed a microfluidic platform, “mechano-node-pore sensing” (mechano-NPS), a rapid and multi-parametric cell screening platform, that simultaneously quantifies cell diameter, transit time through a contraction channel, transverse deformation under constant strain, and recovery time after deformation.  This platform efficiently reveals malignant-dependent mechanical phenotypes of cancer and normal epithelial cells, discriminates between sub-lineages of cells with accuracy comparable to flow cytometry, and determines the effects of chronological age and malignant progression on cell elasticity and recovery from deformation – based solely on a cell’s mechanical properties.

Voltage-Sensitive Dyes In Living Cells

96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Comprehensively mapping and recording the electrical inputs and outputs of multiple neurons simultaneously with cellular spatial resolution and millisecond time resolution remains an outstanding challenge in the field of neurobiology. Traditionally, electrophysiology is used to directly measure membrane potential changes. While this technique yields sensitive results, it is invasive and only permits single-cell recording.  VoltageFluor dyes rely on photoinduced electron transfer to effectively report membrane potential changes in cells. This approach allows for fast, sensitive and non-invasive recording of neuronal activity in cultured mammalian neurons and in ex-vivo tissue slices. However, one major limitation of small-molecule dye imaging is the inability to target the dye to specific cells of interest.   UC Berkeley researchers have developed latent voltage sensitive dyes that require a fluorogenic activation step. This new class of VoltageFluor dyes are only weakly fluorescent until being activated in defined cell types via biological processes. In particular, the VoltageFluor dyes described herein comprise a bioreversible group that quenches the fluorescence of the VoltageFluor dye, that upon selective removal by the action of biological processes (e.g., enzymes) thereby activates the fluorescence of the VoltageFluor dye. The researchers found that the new dye facilitated the observation of spontaneous activity in rat hippocampal neurons.  

CARDIAC TISSUE MODELS AND METHODS OF USE THEREOF

96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Tissue engineering approaches have the potential to increase the physiologic relevance of human iPS-derived cells, such as cardiomyocytes (iPS-CM). However, forming Engineered Heart Muscle (EHM) typically requires >1 million cells per tissue. Existing miniaturization strategies involve complex approaches not amenable to mass production, limiting the ability to use EHM for iPS-based disease modeling and drug screening. Micro-scale cardiospheres are easily produced, but do not facilitate assembly of elongated muscle or direct force measurements.   UC Berkeley researchers have developed a 3D filamentous fiber matrix that combines features of EHM and cardiospheres: Micro-Heart Muscle (μHM) arrays, in which elongated muscle fibers are formed in an easily fabricated template, with as few as 2,000 iPS-CM per individual tissue. Within μHM, iPS-CM exhibit uniaxial contractility and alignment, robust sarcomere assembly, and reduced variability and hypersensitivity in drug responsiveness, compared to monolayers with the same cellular composition. μHM mounted onto standard force measurement apparatus exhibited a robust Frank-Starling response to external stretch, and a dose-dependent inotropic response to the β-adrenergic agonist isoproterenol.  

Simple And Low-Cost Pseudo-Halbach Magnets For NMR

Nuclear magnetic resonance (NMR) spectroscopy exploits the magnetic properties of certain atomic nuclei to determine the physical and chemical properties of the substances in which they are contained. It can provide detailed information about the structure, dynamics, reaction state, and chemical environment of molecules, where the magnetic field is used to polarize atomic nuclei prior to detection of their signals. In conventional NMR magnet design, the homogeneity of the field is a principal consideration and should be made as uniform as possible to obtain the most informative results and best data quality. Researchers from UC Berkeley have developed an assembly of magnetized prisms with an orientation pattern to generate the strongest available magnetic field.  The design is based on the priority of achieving the strongest available field over a given volume irrespective of the homogeneity.  The team has designed and made a compact 2 T magnet to fulfil these objectives.

Method For Imaging Neurotransmitters In Vitro and In Vivo Using Functionalized Carbon Nanotubes

Neurotransmitters play a central role in complex neural networks by serving as chemical units of neuronal communication.  Quantitative optical methods for the detection of changes in neurotransmitter levels has the potential to profoundly increase our understanding of how the brain works. Therapeutic drugs that target neurotransmitter release are used ubiquitously to treat a vast array of brain and behavioral disorders.  For example, new methods in this sphere could provide a new platform by which to validate the function of drugs that alter modulatory neurotransmission, or to screen antipsychotic and antidepressant drugs.  However, currently in neuroscience, few optical methods exist that can detect neurotransmitters with high spatial and temporal resolution in vitro or in vivo.  Brain tissue also readily scatters visible wavelengths of light currently used to perform biological imaging, and neuronal tissue and has an abundance of biomolecules that are chemically or structurally similar and therefore hard to specifically distinguish.  Furthermore, neurotransmission relevant processes occur at challenging spatial  and temporal scales.    UC Berkeley investigators have developed polymer-functionalized carbon nanotubes for in vitro and in vivo quantification of extracellular modulatory neurotransmitter levels using optical detectors. The method uses the fluorescent optical properties of polymer-functionalized carbon nanotubes to selectively report changes in concentration of specific neurotransmitters. The scheme is novel in that the detection method applies to wide variety of specific neurotransmitters, it is an optical method and therefore gives greater spatial information, and enables the potential for imaging of one or more neurotransmitters. The optical method also produces less damage to the surrounding tissue than methods that implant electrodes or cells and allows high resolution localization with other methods of optical investigation. The invention takes advantage of favorable fluorescence properties of carbon nanotubes, such as carbon nanotube emission in the near infrared and infinite fluorescence lifetime.  The near infrared emission scatters less than shorter wavelengths, enabling greater signal recovery from deeper tissue, and allows greater compatibility with other techniques. The optical properties also enable long term potentially even chronic use. 

Highly Stable Nanoscale Disk Assemblies Of The Tobacco Mosaic Virus For Applications In Drug Delivery And Disease Imaging

96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Self-assembling protein nanomaterials derived from viruses have properties that make them useful for applications in drug delivery, disease imaging and diagnostics. These properties include uniform sizes and shapes, biodegradability, and multiple sets of functional handles for chemical manipulation. Intact virus nanoparticles have been functionalized for applications in drug delivery in vivo, however, the injection of replication-competent viruses into subjects have limited their clinical appeal. The development of spherical and rod-shaped virus nanoparticles has in both cases resulted in differential tumor accumulation, demonstrating the need to further expand the shape library of protein nanomaterials. However, expressing non-spherical virus-based protein nanomaterials without the genetic material that functions as a backbone to the assembly architecture can lead to significant challenges including poly-diversity in size and shape, and change in assembly behavior in response to different conditions such as pH and ionic strength.   UC Berkeley researchers have developed a self-assembling nanoscale disk derived from a mutant of a recombinantly expressed viral coat protein. The disks display highly stable double-disk assembly states. The researchers functionalized the disks with the chemotherapy drug doxorubicin (DOX) and further modified the disks for improved solubility.  The functionalized disks displayed cytotoxic properties similar to those of DOX alone when incubated with U87MG glioblastoma cells, but the unmodified disks did not cause any cytotoxicity.

RNA-directed Cleavage and Modification of DNA using CasY (CRISPR-CasY)

96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} The CRISPR-Cas system is now understood to confer bacteria and archaea with acquired immunity against phage and viruses. CRISPR-Cas systems consist of Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a CRISPR array, which includes direct repeats flanking short spacer sequences that guide Cas proteins to their targets.  Class 2 CRISPR-Cas are streamlined versions in which a single Cas protein bound to RNA is responsible for binding to and cleavage of a targeted sequence. The programmable nature of these minimal systems has facilitated their use as a versatile technology that is revolutionizing the field of genome manipulation.  Current CRISPR Cas technologies are based on systems from cultured bacteria, leaving untapped the vast majority of organisms that have not been isolated.  There is a need in the art for additional Class 2 CRISPR/Cas systems (e.g., Cas protein plus guide RNA combinations).     UC Berkeley researchers discovered a new type of Cas protein, CasY.  CasY is short compared to previously identified CRISPR-Cas endonucleases, and thus use of this protein as an alternative provides the advantage that the nucleotide sequence encoding the protein is relatively short.  CasY utilizes a guide RNA to perform double stranded cleavage of DNA. The researchers introduced CRISPR-CasY into E. coli, finding that they could block genetic material introduced into the cell.  Further research results indicated that CRISPR-CasY operates in a manner analogous to CRISPR-Cas9, but utilizing an entirely distinct protein architecture containing different catalytic domains.   CasY is also expected to function under different conditions (e.g., temperature) given the environment of the organisms that CasY was expressed in.  Similar to CRISPR Cas9, CasY enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation.   

RNA-directed Cleavage and Modification of DNA using CasX (CRISPR-CasX)

96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} The CRISPR-Cas system is now understood to confer bacteria and archaea with acquired immunity against phage and viruses. CRISPR-Cas systems consist of Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a CRISPR array, which includes direct repeats flanking short spacer sequences that guide Cas proteins to their targets.  Class 2 CRISPR-Cas are streamlined versions in which a single Cas protein bound to RNA is responsible for binding to and cleavage of a targeted sequence. The programmable nature of these minimal systems has facilitated their use as a versatile technology that is revolutionizing the field of genome manipulation.  Current CRISPR Cas technologies are based on systems from cultured bacteria, leaving untapped the vast majority of organisms that have not been isolated.  There is a need in the art for additional Class 2 CRISPR/Cas systems (e.g., Cas protein plus guide RNA combinations).   UC Berkeley researchers discovered a new type of Cas protein, CasX, from groundwater samples. CasX is short compared to previously identified CRISPR-Cas endonucleases, and thus use of this protein as an alternative provides the advantage that the nucleotide sequence encoding the protein is relatively short.  CasX utilizes a tracrRNA and a guide RNA to perform double stranded cleavage of DNA. The researchers introduced CRISPR-CasX into E. coli, finding that they could block genetic material introduced into the cell.  Further research results indicated that CRISPR-CasX operates in a manner analogous to CRISPR-Cas9, but utilizing an entirely distinct protein architecture containing different catalytic domains.   CasX is also expected to function under different conditions (e.g., temperature) given the environment of the organisms that CasX was expressed in.  Similar to CRISPR Cas9, CasX enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation. 

Compositions and Methods for Inhibiting Stem Cell Aging

96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} By 2050 the number of people in the world that will be aged 65 or older is expected to nearly triple to about 1.5 billion, representing 16% of the world’s population. One aspect of aging involves a diminished capacity to repair tissues after injury. This diminished capacity is evident in certain conditions that occur with aging, such as anemia, sarcopenia (loss of muscle mass), and osteoporosis. Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. Adult stem cells mostly reside in a metabolically inactive quiescent state to preserve their integrity, but convert to a metabolically active proliferative state to replenish the tissue. The signals that trigger stem cells to exit the cell cycle and re-enter quiescence, and the signal transduction leading to the transition remain elusive however.   UC Berkeley researchers have developed methods of reducing or inhibiting or reversing stem cell aging or preventing and/or reversing tissue degeneration or injury by increasing the activity and/or the level of SIRT2 in an adult stem cell or reducing the level of a nucleotide-binding domain and leucine-rich repeat- containing-3 (NLRP3) polypeptide in an adult stem cell.  

Piezoelectric Micromachined Ultrasonic Transducer Device and Methods

Ultrasound transducers have been widely used in applications such as imaging, diagnostics, and treatments or therapy. Piezoelectric micromachined ultrasonic transducers (pMUTs) for medical devices configured to direct sound waves to body tissue have attracted industry attention for their high pressure-to-size-output ratios, small geometry, low manufacturing cost, low driving voltages, low power consumption, and favorable compatibilities with CMOS and consumer electronics. Traditional ultrasound-based methods involve complex, bulky and expensive hardware. single-electrode unimorph pMUTs have less favorable performance characteristics for medical diagnostics and treatment.  Researchers at the University of California, Berkeley, have developed next generation of pMUTs arrays with desirable electromechanical coupling and output efficiencies for medical applications.

C2c2 - A Dual Function Programmable RNA Endoribonuclease

Bacterial adaptive immune systems employ CRISPRs and CRISPR-associated (Cas) proteins for RNA-guided nucleic acid cleavage. Although generally targeted to DNA substrates, the Type VI CRISPR system directs interference complexes against single-stranded RNA substrates and in Type VI CRISPR systems, the single-subunit C2c2 protein functions as an RNA-guided RNA endonuclease.   UC Berkeley researchers have discovered that the CRISPR-C2c2 has two distinct RNase activities that enable both single stranded target RNA detection and multiplexed guide-RNA processing.  These dual RNase functions were found to be chemically and mechanistically different from each other and from the CRISPR RNA processing behavior of the evolutionarily unrelated CRISPR enzyme Cpf1.  Methods for detecting the single stranded target RNA were also discovered using a C2c2 guide RNA and a C2c2 protein in a sample have a plurality of RNAs as well as methods of cleaving a precursor C2c2 guide RNA into two or more C2c2 guide RNAs.  

Diagnostic Colorimetric Assay

0 0 1 183 1047 UC Berkeley 8 2 1228 14.0 Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Times New Roman";} Hyper-accumulation of copper in biological fluids and tissues is a hallmark of pathologies such as Wilson’s and Menkes diseases, various neurodegenerative diseases, and toxic environmental exposure. Diseases characterized by copper hyper accumulation are currently challenging to identify due to costly diagnostic tools that involve extensive technical workup.   To solve these problems, UC Berkeley researches developed a simple yet highly selective and sensitive diagnostic tool along with new materials that can enable monitoring of copper levels in biological fluid samples without complex and expensive instrumentation.  The diagnostic tool includes a robust three-dimensional porous aromatic framework (PAF) densely functionalized with thioether groups for selective capture and concentration of copper from biofluids as well as aqueous samples.  The PAF exhibits high selectivity for copper over other biologically relevant metals, with a saturation capacity reaching over 600 mg/g.  The researchers were able to use the diagnostic tool, which included a colorimetric indicator, to identify aberrant elevations of copper in urine samples from mice with Wilson’s disease and also traced exogenously added copper in serum. 

Optical Phase Retrieval Systems Using Color-Multiplexed Illumination

Light is a wave, having both an amplitude and phase. Our eyes and cameras, however, only see real values (i.e. intensity), so cannot measure phase directly. Phase is important, especially in biological imaging, where cells are typically transparent (i.e. invisible) but yet impose phase delays. When we can measure the phase delays, we get back important shape and density maps.   Researchers at the University of California, Berkeley have developed a new method for recovering both phase and amplitude of an arbitrary sample in an optical microscope from a single image, using patterned partially coherent illumination. The hardware requirements are compatible with most modern microscopes via a simple condenser insert, or by replacing the entire illumination pathway with a programmable LED array, providing flexibility, portability, and affordability, while eliminating many of the trade-offs required by other methods. This enables quantitative imaging of phase from a single image, using partially coherent illumination, and in a way that is flexible and amenable to a variety of existing microscopy systems. 

PHOTO-INDUCED ELECTRON TRANSFER VOLTAGE SENSITIVE DYES

The development of fluorescent indicators for sensing membrane potential can be a challenge.  Traditional methods to measure membrane potential rely on invasive electrodes, however, voltage imaging with fluorescent probes (VF) is an attractive solution because voltage imaging circumvents problems of low- throughput, low spatial resolution, and high invasiveness. Previously reported VF probes/dyes have proven useful in a number of imaging contexts. However, the design scheme for VF dyes remains elusive, due in part to our incomplete understanding of the biophysical properties influencing voltage sensitivity in our VoltageFluor scaffolds.   UC Berkeley researchers have discovered new VF dyes, which are a small molecule platform for voltage imaging that operates via a photoinduced electron transfer (PeT) quenching mechanism to directly image transmembrane voltage changes.   The dyes further our understanding of the roles that membrane voltage plays, not only in excitable cells, such as neurons and cardiomyocytes, but also in non-excitable cells in the rest of the body.

Chemical Cocktail For Deriving Myogenic Cells

In postnatal life, growth and repair of skeletal muscle fibers are mediated by the satellite cells. These cells divide at a slow rate to sustain both self-renewal and growth of skeletal muscle tissue. In response to muscle injury, satellite cells divide and fuse to repair or replace the damaged muscular fibers. However, the self-renewal potential of adult satellite cells is limited and is compromised with aging, excessive trauma, or genetic defect as in certain severe muscular dystrophies such as Duchenne muscular dystrophy. In such cases, external interventions are needed.             UC Berkeley researchers have developed a chemical cocktail that allows large number of myogenic stem cells to be derived from, but no limited to, mouse dermal fibroblasts. These myogenic stem cells could then be transplanted into diseased or injured skeletal muscle to promote regeneration and recovery. In addition, the chemicals could be directly delivered into diseased or injured skeletal muscle to promote regeneration in vivo.  The mixture allows large number of patient-specific skeletal muscle cells to be obtained conveniently from non-invasive skin biopsy techniques. The in vitro culture of these skeletal muscle cells can then be used for disease modeling and drug screening purposes.

Versatile Cas9-Mediated Integration Technology

Many advancements to the Cas9 system (both the Cas9 nuclease and the sgRNA sequence) have been made to increase and optimize its efficiency and specificity.  Since many diseases and traits in humans have a complex genetic basis, multiple genomic targets must be simultaneously edited in order for diseases to be cured or for traits to be impacted.  Thus in order for CRISPR/Cas9 to be an effective gene therapeutic technology, huge swathes of the genome must be edited simultaneously, efficiently, and accurately. To address many of these issues, UC Berkeley researchers have developed a system method to rapidly manipulate multiple loci. This system allows for either sequential (maintaining inducible Cas9 present in the genome) or simultaneous (scarless excision) manipulation of Cas9 itself and can be applied to any organism currently utilizing the CRISPR technology.  The system can also be applied conveniently to create genomic libraries, artificial genome sequences, and highly programmable strains or cell lines that can be rapidly (and repeatedly) manipulated at multiple loci with extremely high efficiency.  

Sheet of Disposable Drug Formulation Pouches

University of California, Berkeley has an ornamental design for a sheet of disposable drug formulation pouches.

Metal-Organic Frameworks for H2 Adsorption and Drug Delivery

Metal–organic frameworks (MOFs) are an important class of materials with high internal surface areas and tunable pore environments that make them of interest for a wide variety of potential applications, including gas adsorption and drug delivery. One of the most ubiquitous MOF materials is of the type M2(dobdc) (2,5-dioxido-1,4-benzenedicarboxylate), sometimes referred to as M-MOF-74. The pores of these frameworks can be expanded while preserving the parent framework structure by using ligands and other analogues with multiple phenylene groups.   With an interest in exploring new ligands for expanded MOF-74 architectures, UC Berkeley researschers created a new family of expanded MOF-74 materials using the anti-inflammatory olsalazine acid as a ligand to form M2(olz), where M = Mg, Fe, Co, Ni, and Zn. Upon activation, these materials exhibit the highest Langmuir surface areas among bioactive frameworks. The M2(olz) frameworks contain pore apertures of approximately 27 Å, corresponding to the mesoporous range (≥20 Å). Strong H2 adsorption was observed by gas adsorption studies and in situ infrared spectroscopy, confirming the presence of open metal sites for all but the Zn analogue. The Mg2(olz) framework, which disassembles under physiological conditions to release olsalazine, represents an unprecedented level of loading in a bioactive metal–organic framework of 86 wt % drug. In addition to delivery of olsalazine, the large pores of Mg2(olz) were used to encapsulate a second drug, illustrating the potential of this platform to deliver multiple therapeutic components.  

Rapid Methods for Multi-layer Microfluidic Structures

Microfluidics has rapidly advanced in the fields of chemical and biological research since 1980s due to its unique ability to make low-cost, high-throughput platforms. The most far-reaching breakthrough in microfluidics has been the development of soft-lithography using rigid micromachined molds to shape elastomeric polymers. Among polymeric materials, Polydimethylsiloxane (PDMS) is commonly used due to its numerous ideal properties, including its ease in manufacturing, reasonable cost, as well as strength, transparency, and especially biocompatibility. However, traditional PDMS methods for fabricating microfluidic devices have a unique set of challenges, including long and expensive process times, and feature sophistication limits (e.g. restricted to rectilinear features). To address these challenges, researchers at UC Berkeley have developed novel 3D printing techniques for fully-integrated, multi-layer microfluidic objects to achieve greater system-level functionalities. For demonstration, UC researchers created complex, high-quality geometries in PDMS without the need for a microscope, including thin membranes and rounded channels and while accounting for surface roughness. Their novel processes could enable assembly of microfluidic components into sophisticated 3D architectures, which may provide a new platform for rapidly creating complex microfluidic devices in volume.

Genotyping Bacteria to Predict Social Contact and Structure

Social connectivity has been increasingly recognized as an essential determinant of disease. How individuals form groups and interact is directly linked to the distribution of diseases in the population, a fact highlighted by the recent Ebola epidemic and reemergence of vaccine preventable diseases in the United States. Notably, this applies not only to infectious diseases, where the spread of diseases is sensitive to the structure of the contact network, but also to chronic diseases, where individuals share common exposures.  Unfortunately, the importance of knowing the structure of social networks is matched by the difficulty in accurately measuring them.    UC Berkeley researchers have developed a method to determine the contact network structure of a population by using the microevolution and transmission of commensal bacteria.  As a result, investigators will be able to track chains of transmission more accurately and quickly during epidemic. 

Sleep Circuit Neurons

Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams. The medulla contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation was unclear.   UC Berkelely researchers have discovered that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep.  The researchers inserted am optogenetic switch into the ventral medulla of mice and the GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects.  The researcheres showed these neurons triggered all aspects of REM sleep, including muscle paralysis and the typical cortical activation that makes the brain look more awake than in non-REM sleep.  

CRISPR genome editing of Zygotes (CRISPR-EZ)

0 0 1 214 1224 UC Berkeley 10 2 1436 14.0 Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin;} Easily accessible and efficient methodologies to edit the genomes of organisms are an immense resource to the biological and biomedical research community. Traditionally, engineering of the mammalian genome is achieved by homologous recombination (HR)-mediated sequence substitution in embryonic stem cells (ESCs), a time consuming process that occurs at low frequency. Taking genetically engineering in mice for example, after extensive screening for ESC colonies with the desired genetic modifications, ESCs are microinjected into mouse blastocysts to generate chimeras capable of germline transmission. Such chimera mice are then crossed to wild-type mice to generate heterozygous offspring (F1), which are then intercrossed to yield homozygous mutant mice (F2) that can be subjected to phenotypic analyses. Despite the wide use of this technology to generate transgenic mice, the low efficiency of HR in ESCs, the laborious process of screening, the technical difficulty of microinjection, and the nature of the mouse life cycle make this approach a lengthy and costly process.   UC Berkeley researchers developed methods for modifying the genome of a mammalian zygote by introducing a ribonucleoprotein complex (RNP) to the zygote via electroporation.  Suitable genome editing nucleases were found to be CRISPR/Cas endonucleases (e.g., class 2 CRISPR/Cas endonucleases such as a type II, type V, or type VI CRISPR/Cas endonucleases.  

Dry-Eye Formulation

The sensation of ocular discomfort commonly referred to as “dry eye” can be caused by various factors. The principal causative factors are (a) increased tear-evaporation rates attributable to meibomian gland dysfunction and insufficient/unbalanced tear-lipid films; (b) inadequate tear-aqueous production attributable to aging, medical procedures performed on the cornea (e.g., LASIK), or other general health conditions (e.g., autoimmune diseases); (c) environmental irritants (e.g., dust, smoke, wind, sun, or low humidity); and (d) eye strain attributable to extended viewing of computer monitors or other working environment-related factors. There are many different artificial-eye drops marketed and prescribed or recommended by medical practitioners to decrease dry-eye sensations. Unfortunately, all provide only short-term or no effects at all on tear-film stability and evaporation rates. Moreover, many artificial-tear formulations contain petrochemicals, (e.g., mineral oil) which have nothing in common with natural lipids comprising human tear-lipid films and might be potentially harmful to the eye.   Researchers at UC Berkeley have developed bicontinuous microemulsion formulations capable of delivering the components necessary to counteract compromised stability of tear-lipid layers and thus enhance the stability of entire tear films. These bicontinuous microemulsion components disperse spontaneously into a physical state that makes the microemulsion completely miscible with both human tear aqueous and human tear lipids. The components of these microemulsions are chemically identical or very close to natural tear lipids and tear aqueous and thus are completely biocompatible with human tear films. The lipids used in this formulation are biodegradable, and human tear enzymes will be able to metabolize these bicontinuous microemulsion lipids.  

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