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Nowhere is prompt and effective medical treatment more important than on the battlefield, where injuries are severe and conditions dangerous. Soldiers are vulnerable to many injuries on the battlefield, the most common combat wounds include: Blast wounds caused by landmines, grenades, IEDs (improvised explosive devices), and suicide bombings where the Amputation rates are high. Other are Gunshot and shrapnel wounds and Head injuries and fractured bones. Blast injuries, burns, and other wounds experienced by warfighters often catastrophically damage their bones, skin, and nerves, resulting in months to years of recovery for the most severe injuries and often returning imperfect results. This long and limited healing process means prolonged pain and hardship for the patient, and a drop in readiness for the military.
Blast injuries, burns, and other wounds experienced by warfighters often catastrophically damage their bones, skin, and nerves, resulting in months to years of recovery for the most severe injuries and often returning imperfect results. This long and limited healing process means prolonged pain and hardship for the patient, and a drop in readiness for the military.
Combat wounds are much more complex because of higher contamination, mostly resulting from the environment where the wound occurred. The challenge and complexity of combat wounds are the large wound size and the heavy amount of drainage. Faster wound healing time or surgical closure is indicated because of painful dressing changes and risk of infection. Wound care has evolved immensely throughout the years in the military arena. Today, the military is using the latest technologies, such as digital imaging and telemedicine. This allows them to send combat wound images from the battlefield or to prepare the hospital site for their injured soldier. In previous wars, troops who lost limbs on the battlefield often died from blood loss. But today, better first aid training and faster medevac keep many more troops alive, with a significant number returning to active duty.
The current standard of care when working with a combat wound are:
- Impregnated polyhexamethylene biguanide gauze dressings
- Silver dressings – antimicrobial properties
- Negative pressure wound therapy – less frequent dressing changes, and controls high amounts of exudate
- Moisture sensors – allows dressing decisions without disturbing the dressing
Although recent experimental treatments offer some hope for expedited recovery, many of these new approaches remain static in nature. For instance, some “smart” bandages emit a continuous weak electric field or locally deliver drugs. Alternatively, hydrogel scaffolds laced with a drug can recruit stem cells, while decellularized tissue re-seeded with donor cells from the patient help avoid rejection by the host’s immune system. These newer approaches may indeed encourage growth of otherwise non-regenerative tissue, but because they do not adapt to the changing state of a wound, their impact is limited.
However, these approaches are passive approaches, Under current medical practice, physicians provide the conditions and time for the body to either heal itself when tissues have regenerative capacity or to accept and heal around direct transplants. Most people are familiar with interventions that include casts to stabilize broken bones or transplants of healthy ligaments or organs from donors to replace tissues that do not regenerate. Passive approaches often result in slow healing, incomplete healing with scarring, or, in some unfortunate cases, no healing at all. Blast injuries in particular seem to scramble the healing processes; 23 percent of them will not fully close. Moreover, research shows that in nearly two thirds of military trauma cases — a rate far higher than with civilian trauma injuries — these patients suffer abnormal bone growth in their soft tissue due to a condition known as heterotopic ossification, a painful experience that can greatly limit future mobility.
DARPA launched the Bioelectronics for Tissue Regeneration (BETR) program in 2019 that represent a sharp break from traditional wound treatments, and even from other emerging technologies to facilitate recovery, most of which are passive in nature. The envisioned BETR technology is aimed at speeding warfighter recovery, and thus resilience, by directly intervening in wound healing. DARPA believes that recent advances in biosensors, actuators, and artificial intelligence could be extended and integrated to dramatically improve tissue regeneration. To achieve this, the new Bioelectronics for Tissue Regeneration (BETR) program asks researchers to develop bioelectronics that closely track the progress of the wound and then stimulate healing processes in real time to optimize tissue repair and regeneration. DARPA believes that recent advances in biosensors, actuators, and artificial intelligence could be extended and integrated to dramatically improve tissue regeneration.
To do this, researchers will build an adaptive system that uses actuators to biochemically or biophysically stimulate tissue, sensors to track the body’s complex response to that stimulation, and adaptive learning algorithms to integrate sensor data and dictate intervention to the actuators. After establishing this closed-loop control over physiological processes, BETR researchers will integrate these devices into a single platform that guides the tissue in real-time along an optimal growth pathway.
Paul Sheehan, the BETR program manager, described his vision for the technology as “not just personalized medicine, but dynamic, adaptive, and precise human therapies” that adjust to the wound state moment by moment to provide greater resilience to wounded warfighters. “Wounds are living environments and the conditions change quickly as cells and tissues communicate and attempt to repair,” Sheehan said. “An ideal treatment would sense, process, and respond to these changes in the wound state and intervene to correct and speed recovery. For example, we anticipate interventions that modulate immune response, recruit necessary cell types to the wound, or direct how stem cells differentiate to expedite healing.”
“Wounds are living environments and the conditions change quickly as cells and tissues communicate and attempt to repair,” Sheehan said. “An ideal treatment would sense, process, and respond to these changes in the wound state and intervene to correct and speed recovery. For example, we anticipate interventions that modulate immune response, recruit necessary cell types to the wound, or direct how stem cells differentiate to expedite healing.”
DARPA anticipates that successful teams will include expertise in bioelectronics, artificial intelligence, biosensors, tissue engineering, and cellular regeneration. Further, DARPA encourages proposals that address healing following osseointegration surgery, which is often necessary to support the use of advanced prosthetics by wounded warfighters.
The Three Stages of Wound Healing
Wounds are classified as acute or chronic depending on how long they take to heal. Acute wounds heal without complication in a relatively predictable amount of time. Chronic wounds take longer to heal and often involve some complications. Clean wounds have no foreign materials or debris inside. Contaminated wounds (also known as infected wounds) might contain dirt, bacteria or other foreign materials.
Wounds generally go through three stages as they repair. Wound healing is not a straight line from A to Z – wounds can progress both forwards and backwards on the road back to health, and how they do so will depend on several outside factors including age, nutrition, Obesity, Repeated trauma, and medication.
During the Inflammatory Phase the body produces a natural response (inflammation) to the injury and forms a clot to stop the bleeding. Blood vessels dilate to allow essential cells (e.g. antibodies, white blood cells, growth factors, enzymes, and nutrients) to reach the wounded area. These cells create swelling, heat, pain, and redness, or the “inflammation” for which the phase is named.
The Proliferation Phase is when the wound is rebuilt. The wound contracts as a new network of blood vessels are constructed so that the tissue can receive sufficient oxygen and nutrients. In healthy stages of wound healing, the tissue is pink or red and uneven in texture and does not bleed easily. Dark tissue can be a sign of infection. Near the end of the proliferative stage, new skin cells resurface the injury.
Finally, the Maturation Phase is when the wound fully closes and the scar begins to fade. This “remodelling” generally begins about 21 days after an injury and can continue for a year or more, however the healed wound area will always be weaker than the uninjured skin, generally only regaining 80% of the original tensile strength.
Speeding Up the Healing Process
MIT Tehnology review reported in 2011 that Researchers at Tufts University are developing agents that, applied to open sores, could someday help chronic wounds heal successfully, and speed the normal healing process.
The wound-healing agents target angiogenesis, the process of blood vessel growth. “If you can’t build new blood vessels, it’s virtually impossible to heal,” says Ira Herman, the project’s leader and director of the Tufts Center for Innovations in Wound Healing Research. When tissue is damaged, cells migrate into the wounded region and then proliferate to form new vessels that supply oxygen and nutrients to the upper layer of skin. This is one of the processes that stall in chronic wounds.
Two decades ago, Herman and colleagues first showed that an enzyme called collagenase, produced by the bacterium Clostridium histolyticum, could promote the healing process in cultured cells and animals. When added to cultured cells, it spurred the cells to crawl and grow faster. “It essentially created track stars out of laggards,” Herman says. Although humans also produce collagenase, the bacterial enzyme was more effective. The enzyme digests collagen, creating small protein fragments called peptides. The researchers believe that the peptides created by the bacterial enzyme cause a more robust response from cells.
The researchers analyzed which peptides were unique products of the bacterial enzyme, and synthesized several of them to see if they could promote wound healing on their own. Herman says peptides would be easier than enzymes to produce and deliver as treatments. It would also be easier to control their effects, he says.
Elizabeth Ayello, a nurse and wound-care expert at the Excelsior College School of Nursing, said, “What’s intriguing about this is it speeds up the healing,” which Ayello says could potentially reduce scarring and infections. Such a treatment could be used on battlefields or in rural areas that lack easy access to hospitals. The acceleration of healing, she says, is particularly exciting given the high costs and significant pain that wounds cause patients.
Bioelectronic interface
Recent developments in materials science, electronics and biology of bioelectronic devices have enabled communication with different human tissues and organs. Researchers are developing new devices and approaches for engineering bioelectronic interfaces, for electronic device-human interactions, specifically in the context of the cardiovascular system, nervous system, gastrointestinal tract, skin and musculoskeletal system.
Such systems may require some degree of artificial intelligence, as biological signals can be noisy and machine learning can be a powerful tool for sorting through that kind of data.
BETR technology program
The envisioned BETR technology would represent a sharp break from traditional wound treatments, and even from other emerging technologies to facilitate recovery, most of which are passive in nature. Under current medical practice, physicians provide the conditions and time for the body to either heal itself when tissues have regenerative capacity or to accept and heal around direct transplants. Most people are familiar with interventions that include casts to stabilize broken bones or transplants of healthy ligaments or organs from donors to replace tissues that do not regenerate.
Passive approaches often result in slow healing, incomplete healing with scarring, or, in some unfortunate cases, no healing at all. Blast injuries in particular seem to scramble the healing processes; 23 percent of them will not fully close. Moreover, research shows that in nearly two thirds of military trauma cases — a rate far higher than with civilian trauma injuries — these patients suffer abnormal bone growth in their soft tissue due to a condition known as heterotopic ossification, a painful experience that can greatly limit future mobility.
Paul Sheehan, the BETR program manager, described his vision for the technology as “not just personalized medicine, but dynamic, adaptive, and precise human therapies” that adjust to the wound state moment by moment to provide greater resilience to wounded warfighters.
“To understand the importance of adaptive treatments that respond to the wound state, consider the case of antibiotic ointments,” Sheehan explained. “People use antibiotics to treat simple cuts, and they help if the wound is infected. However, completely wiping out the natural microbiota can impair healing. Thus, without feedback, antibiotics can become counterproductive.”
Recent technologies have begun to close the loop between sensing and intervention, looking for signs of infection such as changes in pH level or temperature to trigger treatment. To date, however, these systems have been limited to monitoring changes induced by bacteria. For BETR, DARPA intends to use any available signal, be it optical, biochemical, bioelectronic, or mechanical, to directly monitor the body’s physiological processes and then to stimulate them to bring them under control, thereby speeding healing or avoiding scarring or other forms of abnormal healing.
By the conclusion of the four-year BETR program, DARPA expects researchers to demonstrate a closed-loop, adaptive system that includes sensors to assess wound state and track the body’s complex responses to interventions; biological actuators that transmit appropriate biochemical and biophysical signals precisely over space and time to influence healing; and adaptive learning approaches to process data, build models, and determine interventions. To succeed, the BETR system must yield faster healing of recalcitrant wounds, superior scar-free healing, and/or the ability to redirect abnormally healing wounds toward a more salutary pathway.
BETR Awards
A multi-institution research team led by the University of Pittsburgh secured a $22 million grant from the Defense Advanced Research Projects Agency (DARPA) to develop a device combining artificial intelligence, bioelectronics and regenerative medicine to regrow muscle tissue, especially after combat injuries. Researchers at Carnegie Mellon University, Northwestern University, Rice University, University of Vermont, University of Wisconsin and Walter Reed National Military Medical Center also are part of this four-year initiative.
When more than 20% of a muscle is damaged, as is common for soldiers wounded in recent overseas conflicts, the tissue can’t regenerate and a stiff scar forms in place of the missing muscle, which often leads to significant disability. “With these severe injuries it’s been drilled into us through all of our training that functional muscle replacement is not possible,” said principal investigator Stephen Badylak, D.V.M., Ph.D., M.D., professor of surgery at Pitt and deputy director of the McGowan Institute for Regenerative Medicine. “The sort of technology we’re developing offers hope where there otherwise would have been no hope.” Badylak envisions creating a device that would change the environment inside larger wounds to help them heal the way smaller wounds do naturally.
Smaller, self-healing wounds typically switch from inflammatory to anti-inflammatory conditions a couple weeks after the initial injury. Badylak imagines kicking larger wounds into anti-inflammatory mode as early as day three or four, and then again a few days later, repeating the cycle until the muscle rebuilds itself, similar to the way fetal wounds heal without forming a scar. All of that would be accomplished by a smart device implanted inside the wound.
The device will monitor key molecular signals at each stage of healing — from the first hours after injury to the days and weeks that follow — and deliver specific molecules at specific times under the direction of artificial intelligence. The first two years of the project will involve developing the device, then the next two years will involve close collaboration with surgeons at Walter Reed, who treat patients with major muscle loss, to refine the design so that it’s suitable for the clinic.
Meanwhile, the researchers will be working with industry partners and the U.S. Food & Drug Administration to identify and clear regulatory hurdles that might slow down clinical translation. For instance, it’s possible to test whether the components of the device are safe to use in the human body while the overall design is evolving. “We’re developing the science and the device in mostly an academic setting,” Badylak said. “If that’s done without consideration of regulatory and industry requirements, patients would never see it because it would remain buried in institutions with no clear path for clinical translation.” One of the companies engaging in this process is ECM Therapeutics, which Badylak spun out of Pitt in 2018 to speed up the clinical translation of several extracellular matrix technologies developed by his lab. Badylak and Pitt both have a financial stake in the company.
