Bio-inspired bleeding control: Synthesized platelet-like nanoparticles created

Artist's rendering of synthetic platelets. Credit: Peter Allen illustration

Stanching the free flow of blood from an injury remains a holy grail of clinical medicine. Controlling blood flow is a primary concern and first line of defense for patients and medical staff in many situations, from traumatic injury to illness to surgery. If control is not established within the first few minutes of a hemorrhage, further treatment and healing are impossible.

At UC Santa Barbara, researchers in the Department of Chemical Engineering and at Center for Bioengineering (CBE) have turned to the human body's own mechanisms for inspiration in dealing with the necessary and complicated process of coagulation. By creating nanoparticles that mimic the shape, flexibility and surface biology of the body's own platelets, they are able to accelerate natural healing processes while opening the door to therapies and treatments that can be customized to specific patient needs.

"This is a significant milestone in the development of synthetic platelets, as well as in targeted drug delivery," said Samir Mitragotri, CBE director, who specializes in targeted therapy technologies. Results of the researchers' findings appear in the current issue of the journal ACS Nano.

The process of coagulation is familiar to anyone who has suffered even the most minor of injuries, such as a scrape or paper cut. Blood rushes to the site of the injury, and within minutes the flow stops as a plug forms at the site. The tissue beneath and around the plug works to knit itself back together and eventually the plug disappears.

But what we don't see is the coagulation cascade, the series of signals and other factors that promote the clotting of blood and enable the transition between a free-flowing fluid at the site and a viscous substance that brings healing factors to the injury. Coagulation is actually a choreography of various substances, among the most important of which are platelets, the blood component that accumulates at the site of the wound to form the initial plug.

"While these platelets flow in our blood, they're relatively inert," said graduate student researcher Aaron Anselmo, lead author of the paper. As soon as an injury occurs, however, the platelets, because of the physics of their shape and their response to chemical stimuli, move from the main flow to the side of the blood vessel wall and congregate, binding to the site of the injury and to each other. As they do so, the platelets release chemicals that "call" other platelets to the site, eventually plugging the wound.

But what happens when the injury is too severe, or the patient is on anti-coagulation medication, or is otherwise impaired in his or her ability to form a clot, even for a modest or minor injury?

That's where platelet-like nanoparticles (PLNs) come in. These tiny, platelet-shaped 

particles that behave just like their human counterparts can be added to the blood flow to supply or augment the patient's own natural platelet supply, stemming the flow of blood and initiating the healing process, while allowing physicians and other caregivers to begin or continue the necessary treatment. Emergency situations can be brought under control faster, injuries can heal more quickly and patients can recover with fewer complications.

"We were actually able to render a 65 percent decrease in bleeding time compared to no treatment," said Anselmo.

According to Mitragotri, the key lies in the PLNs' mimicry of the real thing. By imitating the shape and flexibility of natural platelets, PLNs can also flow to the injury site and congregate there. With surfaces functionalized with the same biochemical motifs found in their human counterparts, these PLNs also can summon other platelets to the site and bind to them, increasing the chances of forming that essential plug. In addition, and very importantly, these platelets are engineered to dissolve into the blood after their usefulness has run out. This minimizes complications that can arise from emergency hemostatic procedures.

"The thing about hemostatic agents is that you have to intervene to the right extent," said Mitragotri. "If you do too much, you cause problems. If you do too little, you cause problems."

These synthetic platelets also let the researchers improve on nature. According to Anselmo's investigations, for the same surface properties and shape, nanoscale particles can perform even better than micron-size platelets. Additionally, this technology allows for customization of the particles with other therapeutic substances -- medications, therapies and such -- that patients with specific conditions might need.

"This technology could address a plethora of clinical challenges," said Dr. Scott Hammond, director of UCSB's Translational Medicine Research Laboratories. "One of the biggest challenges in clinical medicine right now -- which also costs a lot of money -- is that we're living longer and people are more likely to end up on blood thinners. When an elderly patient presents at a clinic, it's a huge challenge because you have no idea what their history is and you might need an intervention."

With optimizable PLNs, physicians would be able to strike a finer balance between anticoagulant therapy and wound healing in older patients, by using nanoparticles that can target where clots are forming without triggering unwanted bleeding. In other applications, bloodborne pathogens and other infectious agents could be minimized with antibiotic-carrying nanoparticles. Particles could be made to fulfill certain requirements to travel to certain parts of the body -- across the blood-brain barrier, for instance -- for better diagnostics and truly targeted therapies.

Additionally, according to the researchers, these synthetic platelets cost relatively less, and have a longer shelf life than do human platelets -- a benefit in times of widespread emergency or disaster, when the need for these blood components is at its highest and the ability to store them onsite is essential.

Further research into PLNs will involve investigations to see how well the technology and synthesis can scale up, as well as assessments into the more practical matters involved in translating the technology from the lab to the clinic, such as manufacturing, storage, sterility and stability as well as pre-clinical and clinical testing.

Source: University of California - Santa Barbara

New biometric watches use light to non-invasively monitor glucose, dehydration, pulse

This schematic diagram shows how the new system can be used to measure a person's glucose levels noninvasively. Credit: Biomedical Optics Express

Monitoring a patient's vital signs and other physiological parameters is a standard part of medical care, but, increasingly, health and fitness-minded individuals are looking for ways to easily keep their own tabs on these measurements. Enter the biometric watch.

In a pair of papers published in The Optical Society's (OSA) open-access journal Biomedical Optics Express, groups of researchers from the Netherlands and Israel describe two new wearable devices that use changing patterns of scattered light to monitor biometrics: one tracks glucose concentration and dehydration levels, and the other monitors pulse.

The glucose sensor is the first wearable device that can measure glucose concentration directly but noninvasively, the authors say.
And while other wearable devices have been made to monitor pulse, the authors claim their new design would be less sensitive to errors when the wearer is in motion, for example while walking or playing sports

Both of the watches described in the two papers make use of the so-called "speckle" effect, the grainy interference patterns that are produced on images when laser light reflects from an uneven surface or scatters from an opaque material. When the material that is scattering the light is moving -- say, in the case of blood flowing through the circulatory system -- "the speckle pattern changes with changes in the flow," explained biomedical engineer Mahsa Nemati, a graduate student in the Optics Research Group at the Delft University of Technology in the Netherlands and the lead author of the Biomedical Optics Express paper on monitoring pulse. Those light variations are a valuable source of information, she says.

The 'Holy Grail' of Diagnostics

In the first paper, bioengineer Zeev Zalevsky of Israel's Bar-Ilan University and his colleagues describe a new wearable biometric system that uses the speckle effect to directly monitor the glucose concentration in the bloodstream, as well as the wearer's relative hydration level.

"Glucose is the holy grail of the world of biomedical diagnostics, and dehydration is a very useful parameter in the field of wellness, which is one of our main commercial aims," Zalevsky said.

The watch-like device consists of a laser to generate a wavefront of light that illuminates a patch of skin on the wrist near an artery, and a camera that measures changes over time in the light that is backscattered off the skin. Unlike other chemicals present in the blood, glucose exhibits a so-called Faraday effect. This means that in the presence of an external magnetic field (generated by a magnet attached to the device) the glucose molecule alters the polarization of the wavefront and thus influences the resulting speckle patterns. 
Analyzing these changing patterns provides a direct measurement of the glucose concentration. Because one of the main signs of mild to moderate dehydration is muscle weakness, which will alter the strength of the signals, the same device can also be used to indicate the relative dehydration level of the user as it changes over time.

Zalevsky and his colleagues are now working to reduce the margin of error in the device's readings. "Around 96 percent of our in vivo measurements were within a range of 15 percent deviation from the readout of a medical reference glucometer device," Zalevsky noted. "The main factor for errors now is the stability of our device on the wrist of the user. We are currently investing efforts in deriving proper calibration and motion cancellation procedures that will allow us to reduce this sensitivity."

Zalevsky says this is the first step toward non-invasive, continuous in vivo measurement of glucose that is based on sensing an effect that is directly related to glucose concentration. The team expects a commercial version of the device to reach the market within two to three years.

Pulse Tracker

In the second Biomedical Optics Express paper, Nemati and her colleagues at Delft and at Phillips Research developed a method that could be used to monitor pulse non-invasively with a sensor that isn't thrown off by the wearer's movement.

Using simulated heart beats generated in milk and measurements performed on the finger of a volunteer, they found that speckle changes can be used to accurately measure flow pulsations -- that is, the heart rate -- even when the light source used to create the speckle pattern is also moving, as would be the case with a wearable biometric sensor. The researchers found that just a couple of pixels from the image were sufficient to extract the pulse rate.

"This paper shows for the first time that a speckle pattern generated from a flowing liquid can give us the pulsation properties of the flow in spite of motion-induced artifacts," Nemati said. "Sophisticated optics is not necessary to implement this, so the costs for devices can be kept low. Another advantage is that the devices can be non-contact or far from the sample," she added.

The team is currently working with companies to integrate their motion-friendly pulse-monitoring technique into existing sensors, for potential use clinically as well as in sports, Nemati said.

Source: The Optical Society