A new study has discovered a way to significantly accelerate wound healing, which contributes as much as $250 bln in global healthcare costs.
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Wound healing is a big clinical problem, with wounds affecting over 8 million people in the US in 2014 alone. The country’s increasingly aging and obese population has led to the wound closure product market size to grow to $21.4 bln in 2022. This is projected to further increase by more than 4% by the end of this decade.
There’s a reason for these alarming numbers. Skin is the outermost part of our body and is made up of three layers: the epidermis, dermis, and hypo-dermis. It acts as the body’s initial barrier against chemicals, pathogens, mechanical injury, and UV light.
Given that it is the most accessible organ in our body, it’s pretty easy to injure it, leading to a wound. Such injuries are common and can range from minor to severe. They are usually classified as either acute or chronic.
When a wound occurs, our body starts repairing itself through a complex interaction of cellular, chemical, and physical events. This is achieved via two mechanisms: tissue regeneration, which involves replacing the damaged tissue by replicating identical cells, and tissue repair, which repairs the destroyed tissues, but they lose their original structure and specialized function after this.
The sophisticated process of normal healing of an acute wound primarily involves four phases: hemostasis, inflammation, proliferation, and remodeling. Wounds that fail to go through these normal steps tend to remain in a dysregulated inflammatory state.
In stage one, an injury damages the blood vessels, and the body activates platelets and releases growth factors to stop the flow of blood. In stage two, a special type of white blood cell called neutrophils begins to break down dead tissue and remove it. In the latter part of this stage, another type of white blood cell, monocytes, appears and matures into large cells called macrophages, which consume damaged tissue and release cytokines, chemokines, and growth factors.
In stage three, macrophages produce different substances, causing the body to produce new tissue, which fills the wound bed and closes the wound. In stage four, the last stage, the body produces and breaks down collagen for the remodeling of new tissue.
Several factors impair this wound-healing process, including medications, infection, and comorbidities, as well as lifestyle habits, nutritional status, and the pre-existing integrity of the skin.
These factors include smoking, affecting blood flow; alcohol, decreasing immune function; radiation, slowing wound healing; necrosis, causing tissue death; diabetes, leading to complications like peripheral neuropathy and ischemia; obesity, associated with inadequate tissue oxygenation and increased risk of ischemia; steroids, reducing collagen production and fibroblast proliferation; and non-steroidal anti-inflammatory drugs (NSAIDs), halting angiogenesis.
Leveraging the Immune System
Skin injuries disrupt the everyday lives of millions of people, resulting in not just infection and prolonged hospital stays but even death in many cases. A significant amount of resources is being spent on finding effective wound management strategies.
When it comes to wound care, there is an emphasis on finding new therapeutic approaches and technical advancements for acute and chronic wound management. However, this means understanding the science of wound healing and how tissues repair and regenerate following an injury.
While many advances have been made in understanding the intricate process of wound healing, there are more steps that need to be discovered. This is exactly what the new study has achieved. A team of researchers made a major breakthrough as they found a crucial part of the wound healing process that is impaired in conditions such as advanced aging and diabetes.
Successful regenerative medicine treatments actually need to utilize the factors that play a key role in tissue healing. When it comes to the healing of tissues, our immune system plays a vital role here.
As such, adjusting the immune system to promote wound healing has proven very effective. For proper healing, immune components work together to create a complex series of events. Hence, regenerative strategies that control immune components have proved effective in wound healing, especially in cases where immune dysregulation as a result of diseases like diabetes or aging has damaged tissue healing following injury.
These conditions tend to have a negative effect on tissue healing, typically leading to persistent inflammation at the injured site. Diabetic patients actually have a 25% lifetime risk of developing a foot ulcer (DFU), 14% of which progresses to amputation.
“The chances of having this common diabetes-related wound are rising with increased longevity and medical complexity of people with diabetes.”
– ARMI’s Dr Yen-Zhen Lu, the co-lead author of the latest study
Another factor that plays a key role in tissue repair and regeneration is the nervous system. Studies have demonstrated that peripheral nerves are essential in some animal species capable of regenerating tissues. Some studies have used nerve depletion in mice, which has shown that nociceptive neurons promote skin repair and non-peptidergic C-fibers encourage regeneration of adipose tissue (connective tissue extending throughout our body) after UV-induced damage.
Now, nociceptive sensory neurons or nociceptors are specialized primary sensory nerves that sense pain by detecting and responding to toxic stimuli ranging from temperature, inflammation, and chemicals to intense pressure.
These sensory neurons with nerve endings in tissues play an important role as immunoregulators, exerting both protective and harmful effects. For instance, nociceptors can both reduce or heighten inflammation.
Given nociceptors’ ability to modify the immune system and the latter’s critical role in tissue repair and regeneration, the study looked into the significance of peptidergic sensory neurons in healing tissue after an acute injury. The researchers further investigated the use of neuro-immune interactions to advance tissue healing.
The team specifically used muscle and skin as tissue models with nociceptors, in which the immune system helps in repair and regeneration.
Utilizing Sensory Neurons for Tissue Healing
Although there is no clear understanding of how neuroimmune interactions influence the restoration of tissues after a sudden wound, the latest study published in Nature showed that removing or destroying the NaV1.8 nociceptor plays a key role here.
Nav1.8, or voltage-gated sodium channel, is present in the dorsal root ganglion (DRG), a cluster of neurons in the dorsal root of a spinal nerve in small sensory neurons called C-fibers. These C-fibers can be activated by mechanical stimuli and, as such, can carry pain messages. So, Nav1.8’s location can make it a pivotal therapeutic target for the development of new drugs for the treatment of chronic pain.
The study found that, during the healing process, nociceptor endings grow into injured tissues and communicate with immune cells via the neuropeptide CGRP.
“Remarkably, this neuropeptide acts on immune cells to control them, facilitating tissue healing after injury.”
– Lead researcher Mikaël Martino
CGRP, or calcitonin gene-related peptide, is released from sensory nerves and possesses protective mechanisms important for wound healing. It acts through receptor activity-modifying protein 1 (RAMP1) on neutrophils, monocytes, and macrophages to impede management, expedite demise, amplify efferocytosis, and polarize macrophages towards a pro-repair phenotype.
The effects of CGRP on neutrophils (white blood cells that help fight infection) and macrophages (white blood cells that kill microorganisms, remove dead cells, and encourage other immune system cells’ actions) are mediated via the release of thrombospondin-1.
Notably, sensory neurons are important for the distribution of CGRP. This was shown by selectively removing the sensory neurons in mice, which reduced CGRP and considerably diminished the healing of skin wounds and muscle regeneration after injury.
However, being a small peptide, CGRP faces challenges in achieving sustained effects when delivered locally into tissue. Moreover, a high CGRP concentration in the body is not recommended, given its possible off-target effects.
As such, the team designed CGPR and then fused it with an ECM-binding sequence to improve retention and protection without damaging its activity. CGRP variants were finally delivered topically in the skin and via a fibrin hydrogel for muscle.
Upon delivery of 1 μg, both CGRP variants enhanced the extent of wound healing and muscle restoration. A lower dose, 250 ng of the engineered CGRP, provided even better results, while a high dose, 10 μg, contributed to peripheral nociceptive sensitization.
In conclusion, the study found that in mice lacking nociceptors and in those with peripheral neuropathies akin to those observed in diabetic patients, injecting eCGRP (the engineered variety) expedited wound closure and promoted muscle regeneration. The study even mentions that the CGRP application is likely to promote corneal repair.
This shows that by harnessing neuro-immune interactions, we can manage tissues that do not heal due to dysregulated neuroimmune interactions that damage tissue healing.
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Opening New Avenues for Effective Therapies
As we saw, this latest study has made a profound discovery, “the intricate interplay between nociceptors, immune cells, and tissue healing processes,” which has significant implications for advancing our understanding of the tissue healing process after acute injury.
This discovery, according to Associate Professor Martino, has the potential to completely change the face of regenerative medicine by shedding light on “the crucial role of sensory neurons in orchestrating the repair and regeneration of tissues, offering promising implications for improving patient outcomes.”
In addition, these findings can be really helpful for treating poorly healing tissues and chronic wounds. According to Martino, who’s a group leader at the Australian Regenerative Medicine Institute (ARMI) of Monash University and EMBL Australia:
“By harnessing neuro-immune interactions, the team aims to develop innovative therapies that address one of the root causes of impaired tissue healing, offering hope to millions.”
He added that utilizing the potential of “neuro-immuno-regenerative” can lead to the creation of effective therapies as standalone treatments or in combination with existing approaches.
Uncovering the basic mechanisms in the complex aspects of the healing process is fundamental to wound research and finding better and more effective solutions to treat wounds.
Numerous clinical trials are currently underway, focusing on novel drugs and advanced therapies. In particular, hundreds of innovative wound dressings with new and diverse mechanisms of action are in preclinical and clinical development for treating acute and chronic wounds.
In acute wounds, progress is being made in wound dressings that suppress bleeding, absorb fluids that leak out, and close wounds to promote healing. For instance, materials such as alginate, poly(N-isopropylacrylamide), and hydrogels are being explored to create a strongly adhesive wound dressing that accelerates wound contraction.
In chronic wounds that do not progress through the usual healing stages, new bandages target the inflammatory phase, where they tend to linger for too long. Additionally, these bandages restore skin tissue and provide protection against infection. In diabetic wounds, studies aim to jump-start the healing process by inducing acute inflammation through the release of neuropeptide substance P and delivery of a mast cell stabilizer. In diabetic mice, the removal of tissue-damaging proinflammatory factors has been shown to improve tissue regeneration and healing.
Another area of focus is skin wound substitutes for severe burn wounds, where 3D bioprinting is receiving significant attention. Moreover, clinical trials are ongoing in advanced anti-scarring and healing, including those related to stem cells, exosomes, and peptides.
Despite all the progress being made, treating acute and chronic wounds presents many challenges. To tackle them, we require a deeper understanding of the processes driving injury and wound healing in different cases.
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Conclusion
While humans have largely failed to heal their wounds without scars, many animals can regenerate wounds scar-free. Cetaceans, tight-skinned mammals, have exhibited an extraordinary capacity to heal deep soft tissue injuries, although essential information about their wound healing is still lacking. However, salamanders have impressive regenerative abilities. Not only can they heal from both internal and external injuries without scarring, but Salamanders can also regrow their lost limbs.
Notably, animals that can regenerate without any scars tend to have bones that are “very small” and “almost gelatinous” tissues.
It’s not that humans lack these abilities; the incredible ability of human fetuses to heal skin wounds without scarring in the womb has been studied by scientists, an ability we tend to lose after birth. But now, as we discussed above, the discovery of the molecule has accelerated the healing process significantly, up to 2.5 times faster and 1.6 times more muscle regeneration in animal models.
Overall, innovations, breakthroughs, and technological advancement ensure that patients receive the most effective treatment, pointing to a bright future for wound care and advanced healing for humans.
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