Faculty Research 2019
Smoother Joints to Avoid Arthritis
Cornell biomedical engineers are improving the outlook for osteoarthritis patients through better lubrication of joints. A new type of treatment for osteoarthritis, currently in canine clinical trials, shows promise for eventual use in humans. The treatment is a synthetic version of lubricin, a naturally occurring joint lubricant that binds to the surface of cartilage in joints and acts as a cushion during high-impact activities, such as running.
"When the production of that specific lubricant goes down, it creates higher contact between the surfaces of the joint and, over time, it leads to osteoarthritis,” said David Putnam, a professor in the College of Engineering with appointments in the Meinig School and the Smith School of Chemical and Biomolecular Engineering.
The synthetic lubricin is patented through Cornell Technology Licensing; an Ithaca company, iFyber, is working with the researchers to develop the synthetic lubricin therapeutic for humans.
In addition to collaborating on the synthetic lubricin, Lawrence Bonassar, the Daljit S. and Elaine Sarkaria Professor in Biomedical Engineering and in Mechanical and Aerospace Engineering, studied the science behind hyaluronic acid (HA) injections that could change how one of the most popular osteoarthritis treatments is regulated.
The medical community has been divided over exactly how HA injections provide pain relief to osteoarthritis patients. HA products, typically injected into the knee, replace naturally occurring HA that has been depleted, lubricating the joints and preventing bones from rubbing together.
These injections, used for arthritis treatment for more than 30 years, constitute a $1 billion market in the U.S. The products are currently classified by the U.S. Food and Drug Administration (FDA) as class III medical devices, meaning pain relief is achieved through mechanical actions―mainly the reduction in friction between the bones―as opposed to chemical actions. But in December 2018, the FDA declared its intention to consider reclassifying HA products as drugs, citing scientific evidence that suggests HA achieves pain relief through chemical actions within the body. If reclassified, new HA products would face a much steeper challenge in reaching the market, affecting treatment options for the 30 million people in the U.S. who have osteoarthritis.
A new study by Bonassar and colleagues provides new insight on HA’s mode of action. The researchers found the mechanical properties provided by HA’s viscosity, specifically its ability to effectively lubricate cartilage, correlate much more directly to clinical efficacy―i.e., pain relief―than previously thought. (Based on articles by Krishna Ramanujan and Syl Kacapyr)
"Boundary Mode Lubrication of Articular Cartilage With a Biomimetic Diblock Copolymer." Z. Sun, E. Feeney, Y. Guan, S.G. Cook, D. Gourdon, L.J. Bonassar, and D. Putnam. PNAS, 116 (25) 12437-12441.
"Frictional Characterization of Injectable Hyaluronic Acids Is More Predictive of Clinical Outcomes Than Traditional Rheological or Viscoelastic Characterization." E.D. Bonnevie, D. Galesso,C. Secchieri,L.J. Bonassar. PLOS ONE, 14 (5):10.1371.
Brain Blood Flow Finding Gives Hope for Alzheimer's Therapy
You know that dizzy feeling you get when, after lying down for an extended period, you stand up a little too quickly?
That feeling is caused by a sudden reduction of blood flow to the brain, a reduction of around 30 percent. Now imagine living every minute of every day with that level of decreased blood flow.
People with Alzheimer’s disease don’t have to imagine it. The existence of cerebral blood flow reduction in Alzheimer’s patients has been known for decades, but the exact correlation to impaired cognitive function is less understood.
“People probably adapt to the decreased blood flow, so that they don’t feel dizzy all of the time, but there’s clear evidence that it impacts cognitive function,” said Chris Schaffer, associate professor at the Meinig School.
A new study from the joint lab of Schaffer and Nozomi Nishimura, associate professor in the Meinig School, offers an explanation for this dramatic blood flow decrease: white blood cells stuck to the inside of capillaries, the smallest blood vessels in the brain. And while only a small percentage of capillaries experience this blockage, each stalled vessel leads to decreased blood flow in multiple downstream vessels, resulting in a dramatic reduction in overall brain blood flow.
To test the effect of the stalls on performance of memory tasks in Alzheimer’s mice, they were given an antibody that interfered with the adhesion of white blood cells to capillary walls, which caused the stalled capillaries to start flowing again. Brain blood flow increased rapidly and memory function was improved within a few hours, even in aged mice with more advanced stages of Alzheimer’s disease.
“Now that we know the cellular mechanism,” Schaffer said, “it’s a much narrower path to identify the drug or the therapeutic approach to treat it.”
"Neutrophil Adhesion in Brain Capillaries Reduces Cortical Blood Flow and Impairs Memory Function in Alzheimer’s Disease Mouse Models." J.C. Cruz Hernández, O. Bracko, C.J. Kersbergen, V. Muse, M. Haft-Javaherian, M. Berg, L. Park, L.K. Vinarcsik, I. Ivasyk, D.A. Rivera, Y. Kang, M. Cortes-Canteli, M. Peyrounette, V. Doyeux, A. Smith, J. Zhou, G. Otte, J.D. Beverly, E. Davenport, Y. Davit, C.P. Lin, S. Strickland, C. Iadecola, S. Lorthois, N. Nishimura, C.B. Schaffer. Nature Neuroscience. 22(3):413-420, 16, pages 59–62 (2019).
Elegant Trick Improves SINGLE-cell RNA Sequencing
Droplet microfluidics has revolutionized single-cell RNA sequencing, offering a low-cost, high-throughput method for single-cell genomics. However, this method has been limited in its ability to capture complete RNA transcription information.
Researchers at Cornell―led by Iwijn De Vlaminck, assistant professor in the Meinig School―have come up with an elegant, low-cost method that solves that problem. Not only does it push single-cell genomics forward, it may allow for new avenues for studies of infection and immune biology.
Drop-seq, is a method to simultaneously and efficiently characterize the identities of thousands of cells, using nanoliter-scale droplets and attaching a unique identifier to each cell’s RNA.
“Those technologies are very popular because they’ve lowered the cost of these types of analyses and sort of democratized them, made them very cheap and easy to do for many labs,” De Vlaminck said.
Drop-seq, a current method for simultaneously characterizing the identities of thousands of cells, uses nanoliter-scale droplets and attaches a unique identifier to each cell’s RNA. The drawback is that it can only identify a certain type of messenger RNA (mRNA) molecule, which limits the potential scope of analyses. Messenger RNA carries the genetic information copied from DNA in the process of translation.
De Vlaminck and collaborators have come up with a new method, DART-seq (droplet-assisted RNA targeting by single-cell sequencing), a simple, inexpensive twist to the existing Drop-seq protocol.
In Drop-seq, individual cells are encapsulated with labeled microparticles that initiate reverse transcription of cellular mRNA. The De Vlaminck group devised an effective method to enzymatically customize the beads prior to performing conventional Drop-seq analysis, which allows for the recovery and analysis of a greater variety of molecules than are available through Drop-seq sequencing.
In addition, this technology can identify virus-infected cells, and quantify viral and host gene expression, thus enabling examination of the host response to infection at the single-cell level.
"Simultaneous Multiplexed Amplicon Sequencing and Transcriptome Profiling in Single Cells." M. Saikia, P. Burnham, S.H. Keshavjee, M. F. Z. Wang, M. Heyang, P. Moral-Lopez, M.M. Hinchman, C.G. Danko, J. S. L. Parker, & I. De Vlaminck. Nature Methods, 16, pages 59–62 (2019).