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  (Source: Embassy Pictures)
Researchers make major progress in lower spine stimulation but are slowed by lack of equipment

The U.S. Food and Drug Administration (FDA) is both receiving praise and criticism for its handling of research related to the exciting new field of electric stimulation of the lower spine.  These new techniques promise to give paralyzed patients the ability to walk again -- a key therapeutic goal.

The most intensive multi-patient study to date -- conducted by Professor Susan Harkema of the University of Louisville, Kentucky -- is currently concluding and the medical community is carefully eyeing its results.  But recent interviews indicate frustration among biomedical engineers crafting the next generation of stimulation devices. They feel that the FDA's restrictions are making it difficult to apply bleeding edge electronics to this pressing problem.

I. Do Your Legs Have a Mind of Their Own?

The roots of electrical stimulation trace back at least to the start of the twentieth century.  Medical textbooks from a hundred years ago or more indicated a basic understanding that walking and other limb motions in humans and animals was a combination of both control by the brain and by automatic responses (reflexes).

But it was not until the 60s and 70s that researchers discovered that automatic responses might be far more dominant than the brain, a contradiction of the assumption that the brain controls the body.

Published research from this period showed increasing evidence that nerve bundles in animals could be stimulated to produce locomotion even after they were disconnected from the brain.  For example, this 1972 study on walking in crabs showed that gait resulted from current from a combination of muscle contraction and muscle stretching sensors in the limbs.

This study hinted that while the brain (or similar nerve cluster) controlled learning of movement (so called "motor memory"), and sent triggers to initiate a specific kind of movement, from there local clusters of nerves took over and drove motion.

These clusters were sometimes labeled a "cluster pattern generator" (CPG).  Some may recall learning about how dinosaurs had a "second brain" in their tail/lower back.  That "brain" is actually thought to have been a CPG -- no different that the pattern generators found in modern animals ranging from crabs to cats.

A crucial piece of the proof necessary to convince the medical community that walking in animals was mostly automatic came in the form of a 1987 study by Dr. Serge Rossignol (first author) and Professor Jean Barbeau (senior author) of the Université de Montréal (Univ. of Montreal, UdeM), published in the journal Brain Research.  In the study house cats were fully spinalized (sorry, cat lovers) using a spinal cord-cutting procedure similar to the one outlined in this newer study [PDF] by Prof. Rossignol.  

Walking study
When put on treadmills, walking reflexes were observed in paralyzed cats in a salient 1987 work.
[Image Source: J. Neurosci.]

Remarkably the cats were able to be trained to walk again via being placed on a treadmill during "therapy" sessions.  The cats were unable to stand on their own, but once supported showed off a remarkable ability to learn to walk despite having no communication between the brain and leg nerves.  A key here was that the spinal column was intact, showing that the three crucial necessities to locomotion were balance (partially brain-derived), limb feedback (quasi-automatic, after learning), and mechanical support (derived by the integrity of muscles and the spinal column.  In this case the spine was undamaged, so two out of the three necessary traits were fulfilled, thus cats were able to walk with help on the balance issue.

This study taunted the medical establishment.  Could walking in humans follow a similar pattern?  Could our legs essentially have a "mind of their own" and be only loosely under the control of our brain?

It seemed highly probable that if felines -- a relatively advanced mammal -- had CPGs and automatic gait, humans must have them as well.  But finding evidence of a CPG in primates, much less humans, proved infuriatingly elusive.

II. Humans Aren't So Special After All; We Have Pattern Gen. Just Like the Next Animal

A half decade later and that frustration turned to elation.

The breakthrough came in 1993 when Professor Hans Hultborn (first author) and Professor Jens Bo Nielsen (senior author) of the Univ. of Copenhagen, et al. presented the first evidence of a CPG in a species of marmoset (Callithrix jacchus) at an annual meeting of the Society of Neuroscience in Washington, D.C.

marmoset
Evidence of a CPG in primates was first observed in Marmosets. [Image Source: Flickr/L. Leszczynski]

The work set the medical research community ablaze with excitement.  Within a year The Miami Project -- a group of researchers from the University of Miami seeking a "cure" for human complete and incomplete paralysis -- had published a new study in the journal Brain showing that electrical stimulation to the lower spine could trigger involuntary walking motion in paralzyed humans.

The work by Professor Blair Calancie (first author; now at the State Univ. of New York (SUNY)) and Dr. Barth Green (senior author), was followed by several other studies in the late 1990s.

Miami Project patient   Miami Project
The Miami Project (Chairman Dr. Green is pictured left) was crucial in showing early evidence of a human CPG. [Image Source: Miami Project]

Researchers at Baylor University (BU) in Houston, Texas in 1998 published a study in the Annals of the N.Y. Academies of Science showed further evidence of a human CPG.  Using an electric generator, Dr. Milan Dinitrijevic (first author) (BU) and Dr. Michaela Pinter of the Ludwig Boltzmann Institute for Restorative Neurology and Neuromodulation in Vienna, Austria (senior author), applied currents of frequency of 25 to 60 Hz and an amplitude of 5-9 V to the L2 vertebrae (the second lumbar) of completely paralyzed subjects and observed walking motions. 

Human CPG
The human CPG is thought to be located around the L1-L2 vertebrae.
[Image Source: PVA, modifications: Jason Mick/DailyTech LLC]

Other studies around this time showed that similar autonomous nerve centers in the lower back controlled the mictration (urination) and ejaculation (sexual function) in vertebrates, including primates.

III. Jump Starting the "Second Brain"

Now researchers had a seemingly clear path to rerouting the circuitry of the human body and giving victims of paralysis everything they have lost -- the ability to urinate, experience sexual encounters, stand, and walk -- all without assistance.  But in practice this clear road quickly devolved into a string of disappointments.

Researchers were able to stimulate walking motion in some cases, but were unable to figure out how to consistently and reliable use this physiological parlor trick to reliably restore the abilkity to walk and stand in paralysis victims.  In 2001 Professor Susan Harkema of the University of California (UC) wrote a paper in the journal Neuroscientist detailing these struggles and the potential of so-called "locomotor training" -- trying to trick the human CPG into relearning how to walk in paralysis victims.


A couple years later she moved to the University of Louisville, Kentucky and began pioneering work to expand the scope of locomotor training and lower spine stimulation.  It was not easy to find the equipment to do her work with as she was literally inventing a new field.

She found a potential fit in the RestoreAdvanced Stimulator, a 16 electrode spinal stimulation device by Medtronic, Inc. (MDT) which was FDA approved, but marketed as a means of managing extreme pain.  But its range -- 2 to 100 Hertz and 0 to 10.5 volts -- seemed ideal as it was in the realm of what past researchers observed was necessary to overcome a threshold and stimulate motion.

Medronic Restore AdvancedMedtronic stimulator

Armed with the FDA approved device, Professor Harkema found an ideal patient in Rob Summers, a former top college pitcher who was tragically paralyzed below the neck by a hit-and-run driver.  Project Walk was born.

For six hours a day, Mr. Summers would push through a mentally exhausting regiment of physical therapy.  In December 2009, Professor Harkema obtained the FDA's permission to implant electrodes from a RestoreAdvanced unit into Mr. Summers' lower back.  And it wouldn't take long for that procedure to pay off.

Defying the odds, Mr. Summers stood within three days of the implant surgery.  And within nine months Mr. Summers took his first steps since becoming a paraplegic.  Better still, Mr. Summers' therapy restored his control over bowel, bladder, and sexual function -- allowing him freedoms that most of us take for granted, but which he feared he'd never again enjoy.




Professor Harkema (first author) and UCLA Prof. Reggie Edgerton (senior author) published an account of this terrific success in the June 2011 edition of one of medicine's most prestigious peer-reviewed journals -- Lancet.

A key to this success was not overdoing it with the voltage and frequency.  The results of the work and others since hint that pushing too much voltage into the lower spine actually interferes with the human CPG, scrambling its signals and preventing triggering walking or other useful motions.  The researchers saw their greatest success in inducing locomotor (walking) patterns at around 30-40 Hz and 7 V.  Comments Prof. Edgerton to IEEE Spectrum in a recent interview, "[Before this work] everyone, including us, was hung up on the idea that you have to stimulate at this high level to induce the movement."

Susan Harkema
Professor Susan Harkema (L) and Reggie Edgerton (R) pose with patient Rob Summers at an awards ceremony. [Image Source: Getty Images]

In other words, when it came to tapping into spinal nerves, it wasn't always best to "turn it up to 11", so to speak.

Already an expert in the field Prof. Harkema found that the results with Mr. Summers opened many new doors.  She comments, "I have no problem asking for help now."

IV. Round II: Electrostimulation Trials Expand

Professors Harkema and Edgerton's next goal was to test the procedure on more patients.  As Professor Edgerton stated, "The next big question was, Will you ever see these things in more than one subject?"

The pair last year moved ahead in trying to answer that question.  The pair successfully obtained FDA approval to test the therapy on four more patients.  Candidates were encouraged to submit their names to a pool; winnners were announced in July 2012.  Among the participants was Wyoming native Dustin Shillcox who became a paraplegic at age 26, when he was driving a work van for his family business and flipped the vehicle.

Dustin Shillcox
Dustin Shillcox is Professor Harkema's fourth patient in her electrostimulation trials and was able to stand. [Image Source: IEEE Spectrum]

The first two participants in the second round trial -- known as Patients 2 and 3 -- were able to stand, according to the recent IEEE Spectrum report.  Likewise in February of this year Mr. Shillcox stood for the first time since being paralyzed.  

The feat required a Luke Skywalker-turn-off-your-targeting-computer sort of moment, as researchers only successfully stimulated standing after releasing Mr. Shillcox from a supportive tether that was depriving his legs from the weight-bearing feedback that proved critical in allowing the CPG -- his spinal nerve cluster -- to order his legs to stand.  Sometimes less is more; with less support the CPG received received more feedback and with the help of the electrostimulation allowed Mr. Shillcox to stand with minimal balance support from his helpers.

Dustin Shilcox therapy     
Shilcox therapy    
Dustin Shillcox does physical therapy exercises with Professor Harkema. [Image Source: IEEE Explore]

While the announced preliminary results make it clear that Professor Harkema has manged to consistently stimulate standing motion, it's unclear whether Mr. Shillcox or the other patients have been able to walk or regained control over bowel, bladder, and sexual function like Mr. Summers.

Even as the medical community is carefully watching these benchmarks, Mr. Shillcox says he's doing his best to keep his expectations realistic.  He comments, "I don’t want to be too optimistic, and I’m trying to be prepared for no results at all.  I hope that whatever they find from this research will at least benefit other people."

V. Progress Stymied by Crude Tools

At this point Professor Harkema's research is primarily geared towards physical therapy -- preventing the chronic atrophying of leg muscles in patients with spinal cord injuries (SCIs).  She would love to give patients the tools to walk again, but she acknowledges that with current generation hardware that may be impossible.

The RestoreAdvanced stimulator has 4.3x10^7 combinations.  Each setting requires the stimulator to entirely power off then cycle back on.  A 75 minute trial may only allow 10 test configurations.  Thus in the 170 or so trials involved in a single-patient evaluation as few as 1.7x10^3 configurations may be explored -- or about 4 thousandths of a single percent of the total combinations.

So Prof. Harkema has to curb her expectations and guess smart when it comes to settings.  She particularly bemoans the shutdown/startup requirement, commenting, "You can get really close, and you think the person is almost standing independently, and if you could just shift the field a little you would have it. But you can’t. You have to go to zero. And then everything starts over.  It’s a left-to-right problem. If we get the right leg to step, the left is doing nothing."

WalkProject
Professor Harkema's current hardware has 43 million configurations.  It takes up to 10 minutes to test a single configuration during a therapy session. [Image Source: Harkema Lab]

While stem cells therapies -- regrowing spinal tissue to replace damaged tissue in a patient's spinal cord -- is the most promising route to a full "cure" of paralysis, those efforts remain in the very crudest of stages still, focusing on getting cells to differentiate.

One key problem is finding a source of stem cells.  Embryonic stem cells are the most promising source in some ways, but they also raise ethical issues and may be attacked by a patient's immune system, potentially requiring a patient to go on caustic immune-blocking regiments.  The alternative -- stem cells created by tricking skin cells or other tissues into reverting to stem cell form -- have their own issues.  They can be nearly as flexible as embryonic cells, but they frequently transform into cancer.  Rates of tumorogenesis are so high, that they're not ready for human use -- not yet.

Stem CellsStem cells are a potential long-term full cure, but currently suffer from a number of ethical and technical challenges. [Image Source: NewsOne]

A stop-gap measure would be to create a better spinal simulator that can learn better and trigger actions more quickly via faster output switching.  Such an advanced stimulator could be used on its own, or in combination with an exoskeleton, perhaps allowing a person's limbs to do part of the work, and having a machine exoskeleton assist with balance and a bit of extra effort.

Vanderbilt exoskeleton
Vanderbilt's new exoskeleton is lighter than its rivals and bakes in new capabilities.
[Image Source: Vanderbilt/Parker Hannifin]

Vanderbilt University's Center for Intelligent Mechatronics and medical equipment maker Parker Hannifin Corp. (PH) recently unveiled an exoskeleton designed at exactly such an application.  It's important to recgonize that these two solutions -- electrostimulation and exosuits -- are each imperfect solutions, which ideally should be able to be combined for better results.

VI. Towards a Next-Generation Stimulator

California Institute of Technology (CalTech) mechanical engineering Professor Joel Burdick is working on the firmware/software side, developing algorithms to better guess which combinations of parameters will trigger certain actions [see, for example, this 2008 work on Bayesian sampling and this 2010 publication on when to stimulate the CPG).  Via machine learning, he hopes to cut the search space by orders of magnitude, allowing researchers to pinpoint signals that trigger the CPG into useful actions.

CalTech electrical engineering Professor Yu-Chong Tai is designing a very complex stimulation tool.  One prototype featuring 40 electrodes in a 4 x 10 configuration is being tested at stimulating the CPG in mice.  The array stretches along about 2 centimers of the rodent spine.  A human version woulde be about 5 centimers long -- long enough to stretch across the key L1 and L2 vertebrae -- and would feature around 125 electrodes.  That's about the same surface area as the current RestoreAdvanced implant covers, but it's almost a ten-fold increase in electrodes.

Spinal stimulator
The CalTech stimulator prototype

Those electrodes give finer control -- which Profesor Tai believes may be crucial to trigger complex movements like walking.  But it also expands the necessary search space by orders of magnitude.  A summary of this work was recently published in the Journal of Neuroengineering and Rehabilitation.

At Prof. Harkema's home base -- the University of Louisville, electric engineering Professor John Naber is looking for a milder hardware hack, working on an improved version of the Medtronic stimulator, which would offer greater independent control of the 16 electrodes and the ability to switch states without powering off.  The problem, he says, is that the device may never get to patient tests due to bureaucratic red tape.

While many SCI victims would be happy to sign whatever waivers were necessary to try the device, it must first be approved by the FDA.  And the FDA calls for a rigorous, slow, and expensive testing process for implants.  He comments to IEEE Spectrum, "It’s not like a commercial integrated circuit or product, because of the FDA requirements for human implants."

spinal injury
The new generation of spinal implants are being slowed by red tape at the FDA. [Image Source: Miami Project]

The holdup in human trials of these prototypes is yet another source of criticism for the FDA -- a federal agency often accused of obstructing potential cures to severe diseases like cancer and spinal injuries.

But red tape or not, the work of researchers around the world -- ranging from Denmark to Kentucky to Miami to California -- has given spinal patients hope of healthier lives even if a full cure still awaits.  So that's something to celebrate.  And it's important to acknowledge the contributions -- both of Professor Harkema and her predecessors -- that got the medical community here.

Sources: University of Louisville, IEEE Spectrum





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Ooh, very cool to see this on DT.
By Mint on 10/29/2013 9:01:41 AM , Rating: 3
I'm been at Caltech for years now designing and building spinal cord stimulators for the very same Dr. Edgerton at UCLA.

We work with rats for now, but I know Susan is very eager to get a version of my device in humans down in Louisville. Of course, we need to get FDA approval for that.




RE: Ooh, very cool to see this on DT.
By Mint on 10/29/2013 9:11:53 AM , Rating: 2
Sorry, I was so eager to reply that I didn't read the whole DT piece :) Well done Jason: you went quite deep into this topic!

Dr. Tai is my advisor, and that implant you see with the microelectrode array is my device from a couple years ago. It was an intermediate step between a passive device (i.e. nothing but wires) and our current device: completely wireless. If anyone has any questions, I'll be happy to answer them.

(I'm probably giving away my identity with this info, but whatever...)


RE: Ooh, very cool to see this on DT.
By Lord 666 on 10/29/2013 9:28:18 AM , Rating: 2
Kudos on the ground breaking work. This is the very field that needs additional attention.

Going back to a thread from last week, in your opinion if Apple or another Fortune 50 company with deep pockets and offshore money were to get into biotech, would it help or hurt these types of innovations? My argument was Apple should branch out to biotech and skirt the FDA rules by using their Irish tax sheltered money for r/d.


RE: Ooh, very cool to see this on DT.
By Mint on 10/29/2013 10:25:33 AM , Rating: 5
I know Jason is giving an anti-FDA slant to this piece, and many scientists are frustrated by them, but the reality is that there's a very good basis for it.

People with spinal cord injuries (and many other ailments) are very desperate for cures. It is extremely easy for them to give consent to having anything procedure/implantation, and you quickly run into moral hazards. But we very often see what you're describing, with dodgy experiments starting off in countries with lax standards. Our experiments have uncovered devices and surgery techniques that lead to much higher chances of rats dying, so that's something we want to minimize as much as possible before moving to humans. It's tough to objectively say where we should draw the line.

As for companies branching out, they're only going to do it if they see enough ROI to make up for losses. This type of work is desperate for funding when it's a pie-in-the-sky ideas, and really you need gov't funding to get it off the ground. When they start looking like viable therapies with a decent business model, it's usually specialized VCs that are best at allocating capital for the best ideas rather than an unrelated company like Apple with money to spend.


RE: Ooh, very cool to see this on DT.
By 3DoubleD on 10/29/2013 2:33:25 PM , Rating: 2
Very cool research. Also very cool that DT picked it up and you are a regular here.

I also work heavily in R&D (finished my PhD, now working at a start-up we created) and I'd like to echo what you said about funding. Large companies are generally not interested in the type of research that goes on in academic environments. These are the pie-in-the-sky, real cutting edge ideas that have the potential to be game changers but are largely theoretical and unproven. They also may be costly, requiring specialized equipment, and also prone to delays. Without government funding, these things just wouldn't happen, the ROI is just too terrible for non-government investors. When you demonstrate a technology to a sufficient level and you do a great job selling that technology to some VCs, you might have a start-up on your hand. After that and years of grueling hard work, you might develop a prototype that catches the eye of a larger company and get acquired. That final step is where Apple, Google, Microsoft, Intel, AMD, ect. would come into the picture. They bet on technologies that are already sufficiently developed and lower risk. Sure these companies do lots of development in house, but these projects are rarely as risky because they have to answer to their shareholders.


RE: Ooh, very cool to see this on DT.
By Lord 666 on 10/29/2013 3:13:01 PM , Rating: 2
Thank you for the feedback and much respect for your hard work.

Problem with the government investment is recently it has not worked out well; collapsed solar start-ups and other failed loans. Don't even mention NASA.

Thinking the Calico/SpaceX/Tesla approach might expedite things. Biotech can and will be extremely profitable.


By 3DoubleD on 10/30/2013 1:46:22 PM , Rating: 2
The scale of government investment we are talking about is very different. In the academic environment, we are generally talking about rather small grants from government agencies. As the project grows and the results improve, more government funding may be awarded, but also applicable industries might start to become interested as well.

When you move to a start-up, again the government gets involved. This is likely a small business, so there are standard tax incentives. It also may be a high technology business, so there are incubator systems setup, which are again largely government funded. At this stage you would likely have to show a significant amount of private sector investor support. The government will only grant you money if you have demonstrated that private entities are already interested.

Large corporations like those solar companies that collapsed recently, those companies are far outside the realm of this type of funding. They already have customers, they have a large work force, established manufacturing, ect. Those particular companies failed partly due to illegal market practices in the form of China price fixing panels and in some cases partly due to poor management (which always exists in the real world to some degree); however, the government supporting such a large company through special loans might not have ever been such a great idea anyway.

You bring up Tesla, but they received a DOE loan as well did they not? Again, not saying it was right or wrong, but it is surely a much larger commitment on the government's behalf to fund such large scale companies versus incubating small start-ups. The purpose was most certainly the same: allowing a company to develop a profitable technology and business model, but the risk may be somewhat different, though I wouldn't want to speculate whether it is better or worse (certainly more noticeable/public though).

In the end, the benefit to the government (and the citizens of that country) is that new industries are being created. The more money that is invested into technology that succeed in becoming autonomous, profitable companies the more "high end" jobs that are created and the more developed and diversified your industry will be. There are also repercussions regarding quality of life, efficiency, resource management, security, ect.

It is really easy to look at the calamity of the solar tech companies and say, government investment in helping companies establish themselves is a poor allocation of money. It is a much more complex and expansive effort. Not all start-up technologies need government funding to develop a product and become profitable (eg. software start-ups have relatively small capital expenditures at the beginning). On the other hand, some technologies would perhaps never see the light of day, perhaps in our lifetimes, without it (eg. nanotech or biotech companies). Certainly no one can predict what technologies will make it and those that won't with 100% accuracy, and government funding agencies certainly won't either. Private investors manage that risk by investing later, when the risk is lower. Government funding fills that void between theory and private investment. Some people may see that as reckless spending of their hard earned tax dollars, but I see it as one of the most important and beneficial actions that a government can take.


RE: Ooh, very cool to see this on DT.
By tng on 10/29/2013 4:37:00 PM , Rating: 2
quote:
I know Jason is giving an anti-FDA slant to this piece, and many scientists are frustrated by them, but the reality is that there's a very good basis for it.
I work in several production facilities where they make medical devices (I used to visit Medtronic quite often) and hear the same FDA issues bemoaned everyday. I agree with most of what the FDA requires of these companies, but you do see some of the red tape that is purely a function of the large bureaucracy that the FDA really is.

Without allot of the rules that the FDA imposes, allot of the same people who complain about them would not have a job. Most don't realize that what they make could be made much cheaper in Korea. With that you would lose most of the traceability of the product manufacturing cycle.


By superstition on 10/30/2013 4:21:57 PM , Rating: 2
It's funny to hear these complaints given how ridiculously lax the FDA is on supplement pills, Chinese-sourced foodstuffs, mercury contaminated HFCS (from "mercury-grade" manufacturing), and so on.

It took a woman who retired from the FDA to blow the whistle on the mercury contamination.


By INSEducate on 10/30/2013 11:35:33 AM , Rating: 3
A resource for developers is the nonprofit Neurotech Network of The Society to Increase Mobility, Inc. Its executive director, Jen French, became the first woman in 1999 to receive a neural implant from the Cleveland FES Center to restore limited function to her lower extremities after a partial spinal cord injury. (See more at http://www.neuromodulation.com/neural-prosthetics)... A key issue is whether a development can easily be widely marketed, and with the need to custom-tailor the intervention, this may hamper commercial development although the National Institute of Neurological Disorders and Stroke does have a neural interfaces research program focused on implantable devices for paralysis. One regulatory path (not sure if it applies) is, for conditions that affect small numbers of people, the Humanitarian Device Exemption (if a specific sub-category of a condition is defined very narrowly perhaps that would be a possible pathway). So I agree the return-on-investment comment applies to commercialization of all technologies, if they are to be taken beyond proof-of-concept demonstrations. However I hope you check out the Neurotech Network if this field interests you (linked from link above).


By Spicy Burrito on 10/29/2013 11:01:24 AM , Rating: 2
Created an account just to say how much I appreciate researchers such as yourself. Keep up the good work, your work makes a difference in many lives.


Hmmm
By Cluebat on 10/29/2013 12:26:26 PM , Rating: 2
Frank Herbert was right. This is a basic Bene Gasserit martial arts training goal. Combat using reflex impulse.




By INSEducate on 11/5/2013 12:22:26 PM , Rating: 2
DoubleD3 has some good observations. Meanwhile, the industry association AdvaMed's daily news briefs included this synopsis today from the Wall Street Journal:

"November 5, 2013

ADVAMED SmartBrief
News for medical technology professionals

Medtech VC funding drought hits companies hard
The medical device industry is pursuing more alternative funding arrangements as venture capital backing in the sector is becoming scarce. Medtech entrepreneurs are assuming more debt, as well as looking to overseas family funds and wealthy individuals in the U.S. to back their ideas. Startups are also pursuing companies to acquire them earlier than they would have previously and are quicker to make deals with larger established companies, as in the case of St. Jude Medical's purchase of startup Nanostim this month."




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