Tag: scarring

Controlling Fibrosis with the Right Mechanical Forces

Photo by Kampus Production: https://www.pexels.com/photo/man-in-blue-and-black-crew-neck-shirt-8638036/

The cells in human bodies are subject to both chemical and mechanical forces. But until recently, scientists have not understood much about how to manipulate the mechanical side of that equation. That’s about to change.

“This is a major breakthrough in our ability to be able to control the cells that drive fibrosis,” said Guy Genin, professor of mechanical engineering in the McKelvey School of Engineering at Washington University in St. Louis, whose research was just published in Nature Materials.

Fibrosis is an affliction wherein cells produce excess fibrous tissue. Fibroblast cells do this to close wounds, but the process can cascade in unwanted places. Examples include cardiac fibrosis; kidney or liver fibrosis, which precedes cancer; and pulmonary fibrosis, which can cause major scarring and breathing difficulties. Every soft tissue in the human body, even the brain, has the potential for cells to start going through a wound-healing cascade when they’re not supposed to, according to Genin.

The problem has both chemical and mechanical roots, but mechanical forces seem to play an outsized role. WashU researchers sought to harness the power of these mechanical forces, using a strategic pull and tug in the right mix of directions to tell the cell to shut off its loom of excess fibre.

In the newly published research, Genin and colleagues outline some of those details, including how to intervene in tension fields at the right time to control how cells behave.

“The direction of the tension these cells apply matters a lot in terms of their activation state,” said Nathaniel Huebsch, an associate professor of biomedical engineering at McKelvey Engineering and co-senior author of the research, along with Genin and Vivek Shenoy at the University of Pennsylvania.

The forces

The human body is constantly in motion, so it should come as no surprise that force can encode function in cells. But what forces, how much force and in which direction are some of the questions that the Center for Engineering MechanoBiology examines.

“The magnitude of tension will affect what the cell does,” Huebsch said. But tension can go in many different directions. “The discovery that we present in this paper is that the way stress pulls in different directions makes a difference with the cell,” he added.

Pulling in multiple directions in a nonuniform manner, called tension anisotropy (imagine a taffy pull) is a key force in kicking off fibrosis, the researchers found.

“We’re showing, for the first time, using a structure with a tissue, we’re able to stop cell cytoskeletons from going down a pathway that will cause contraction and eventual fibrosis,” Genin said.

Huebsch, who pioneered microscopic models and scaffolds for testing these tension fields that act on cells, explained that tentacle-like microtubules establish tension by emerging and casting out in a direction. Collagen around the cell pulls back on that tubule and becomes aligned with it.

“We discovered that if you could disrupt the microtubules, you would disrupt that whole organization and you would potentially disrupt fibrosis,” Huebsch said.

And, though this research was about understanding what goes wrong to cause fibrosis, there is still much to learn about what goes right with fibroblasts, connective tissue cells, especially in the heart, he added.

 “In tissues where fibroblasts are typically well aligned, what is stopping them from activating to that wound-healing state?” Huebsch asked.

Personalised treatment plans

Along with finding ways to prevent or treat fibrosis, Genin and Huebsch said doctors can look for ways to apply this new knowledge about the importance of mechanical stress to treatment of injuries or burns. The findings could help address the high fail rate for treatments of elderly patients with injuries that require reattaching tendon to bone or skin to skin.

For instance, in rotator cuff injuries, there is compelling evidence that patients must start moving their arm to recover function, but equally compelling evidence that patients should immobilise the arm for better recovery. The answer might depend on the amount of collagen a patient produces and the stress fields at play at the recovery site.

By understanding the multidirectional stress fields’ impact on the cell structure, doctors may be able to look at specific patients’ repair and determine a personalised treatment plan.

For instance, a patient who has biaxial stress coming from two directions at the site of injury will potentially need to exercise more to trigger cell repair, Genin said. However, another patient showing signs of uniaxial stress, meaning stress is pulling only one direction, any movement could over-activate cells, so in that case, the patient should keep the injury immobilised. All that and more is still to be worked out and confirmed, but Genin is excited to begin.

“The next generation of disease we’re going to be conquering are diseases of mechanics,” Genin said.

Source: Washington University in St. Louis

An Experimental Drug to Prevent Post-heart Attack Heart Failure

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Scientists at UCLA have developed a first-of-its-kind experimental therapy that has the potential to enhance heart repair following a heart attack, preventing the onset of heart failure. After a heart attack, the heart’s innate ability to regenerate is limited, causing the muscle to develop scars to maintain its structural integrity. This inflexible scar tissue, however, interferes with the heart’s ability to pump blood, leading to heart failure in many patients – 50% of whom do not survive beyond five years.

The new therapeutic approach aims to improve heart function after a heart attack by blocking a protein called ENPP1, which is responsible for increasing the inflammation and scar tissue formation that exacerbate heart damage. The findings, published in Cell Reports Medicine, could represent a major advance in post-heart attack treatment.

The research was led by senior author Dr Arjun Deb, a professor of medicine and molecular, cell and developmental biology at UCLA.

“Despite the prevalence of heart attacks, therapeutic options have stagnated over the last few decades,” said Deb, who is also a member of the UCLA Broad Stem Cell Research Center. “There are currently no medications specifically designed to make the heart heal or repair better after a heart attack.”

The experimental therapy uses a therapeutic monoclonal antibody engineered by Deb and his team. This targeted drug therapy is designed to mimic human antibodies and inhibit the activity of ENPP1, which Deb had previously established increases in the aftermath of a heart attack.

The researchers found that a single dose of the antibody significantly enhanced heart repair in mice, preventing extensive tissue damage, reducing scar tissue formation and improving cardiac function. Four weeks after a simulated heart attack, only 5% of animals that received the antibody developed severe heart failure, compared with 52% of animals in the control group.

This therapeutic approach could become the first to directly enhance tissue repair in the heart following a heart attack; an advantage over current therapies that focus on preventing further damage but not actively promoting healing. This can be attributed to the way the antibody is designed to target cellular cross-talk, benefitting multiple cell types in the heart, including heart muscle cells, the endothelial cells that form blood vessels, and fibroblasts, which contribute to scar formation. 

Initial findings from preclinical studies also show that the antibody therapy safely decreased scar tissue formation without increasing the risk of heart rupture – a common concern after a heart attack. However, Deb acknowledges that more work is needed to understand potential long-term effects of inhibiting ENPP1, including potential adverse effects on bone mass or bone calcification. 

Deb’s team is now preparing to move this therapy into clinical trials. The team plans to submit an Investigational New Drug, or IND, application to the U.S. Food and Drug Administration this winter with the goal of beginning first-in-human studies in early 2025. These studies will be designed to administer a single dose of the drug in eligible individuals soon after a heart attack, helping the heart repair itself in the critical initial days after the cardiac event.

While the current focus is on heart repair after heart attacks, Deb’s team is also exploring the potential for this therapy to aid in the repair of other vital organs.

“The mechanisms of tissue repair are broadly conserved across organs, so we are examining how this therapeutic might help in other instances of tissue injury,” said Deb, who is also the director of the UCLA Cardiovascular Research Theme at the David Geffen School of Medicine. “Based on its effect on heart repair, this could represent a new class of tissue repair-enhancing drugs.”

Scarring after Spinal Cord Injury is More Complex than Previously Thought

Fibrotic scar 14d after spinal cord injury, red – Col1a1+ perivascular fibroblast derived cells Photo: Daniel Holl

New research has found that scar formation after spinal cord injuries is more complex than previously thought. Scientists at Karolinska Institutet have identified two types of perivascular cells as key contributors to scar tissue, which hinders nerve regeneration and functional recovery. These findings, published in Natural Neuroscience, are also relevant for other brain and spinal cord injuries and could lead to targeted therapies for reducing scarring and improving outcomes.

The central nervous system (CNS) has very limited healing abilities. Injuries or autoimmune diseases like multiple sclerosis often lead to permanent functional deficits. 

Regardless of the injury’s cause, the body responds by forming a boundary around the damaged tissue, which eventually becomes permanent scar tissue. 

Two contributing cell types

While scar tissue seals the damaged area, it also prevents functional repair. After spinal cord injuries, scar tissue blocks the regeneration of nerve fibers that connect the brain with the body, resulting in paralysis after severe injuries.

The research team led by Christian Göritz at Karolinska Institutet has made significant progress in understanding how scar tissue forms in the CNS. The group now identified two distinct types of perivascular cells, which line different parts of blood vessels, as the major contributors to fibrotic scar tissue after spinal cord injury. Depending on the lesion’s location, the two identified cell types contribute differently.

“We found that damage to the spinal cord activates perivascular cells close to the damaged area and induces the generation of myofibroblasts, which consequently form persistent scar tissue,” explains first author Daniel Holl, researcher at the Department of Cell and Molecular Biology.

By examining the process of scar formation in detail, the researchers hope to identify specific therapeutic targets to control fibrotic scarring.

Transplanted Hair Follicles Successfully Reduced Scars

Photo by Diana Polekhina on Unsplash

By treating skin scars in three volunteers with hair follicle transplants, researchers found that the scarred skin began to behave more like uninjured skin. According to the results published in Nature Regenerative Medicine, the scarred skin harboured new cells and blood vessels, remodelled collagen to restore healthy patterns, and even expressed genes found in healthy unscarred skin.

The findings could lead to better treatments for scarring both on the skin and inside the body, leading to hope for patients with extensive scarring, which can impair organ function and cause disability.

Lead author Dr Claire Higgins, of Imperial’s Department of Bioengineering, said: “After scarring, the skin never truly regains its pre-wound functions, and until now all efforts to remodel scars have yielded poor results. Our findings lay the foundation for exciting new therapies that can rejuvenate even mature scars and restore the function of healthy skin.”

Hope in hair

Scar tissue in the skin lacks hair, sweat glands, blood vessels and nerves, impairing temperature regulation and sensation. Scarring can also hinder movement as well as potentially causing discomfort and emotional distress.

Compared to scar tissue, healthy skin undergoes constant remodelling by the hair follicle. Hairy skin heals faster and scars less than non-hairy skin- and hair transplants had previously been shown to aid wound healing. Inspired by this, the researchers hypothesised that transplanting growing hair follicles into scar tissue might induce scars to remodel themselves.

To test their hypothesis, Imperial researchers worked with Dr Francisco Jiménez, lead hair transplant surgeon at the Mediteknia Clinic and Associate Research Professor at University Fernando Pessoa Canarias, in Gran Canaria, Spain. They transplanted hair follicles into the mature scars on the scalp of three participants in 2017. The researchers selected the most common type of scar, called normotrophic scars, which usually form after surgery.

They took and microscope imaged 3mm-thick biopsies of the scars just before transplantation, and then again at two, four, and six months afterwards.

The researchers found that the follicles inspired profound architectural and genetic shifts in the scars towards a profile of healthy, uninjured skin.

Dr Jiménez said: “Around 100 million people per year acquire scars in high-income countries alone, primarily as a result of surgeries. The global incidence of scars is much higher and includes extensive scarring formed after burn and traumatic injuries. Our work opens new avenues for treating scars and could even change our approach to preventing them.”

Architects of skin

After transplantation, the follicles continued to produce hair and induced restoration across skin layers.

Scarring causes the epidermis to thin out, leaving it vulnerable to tears. At six months post-transplant, the epidermis had doubled in thickness alongside increased cell growth, bringing it to around the same thickness as uninjured skin.

The next skin layer down, the dermis, is populated with connective tissue, blood vessels, sweat glands, nerves, and hair follicles. Scar maturation leaves the dermis with fewer cells and blood vessels, but after transplantation the number of cells had doubled at six months, and the number of vessels had reached nearly healthy-skin levels by four months. This demonstrated that the follicles inspired the growth of new cells and blood vessels in the scars, which are unable to do this unaided.

Scarring also increases the density of collagen fibres, causing them to align and make the scar stiffer. The hair transplants reduced the fibre density, allowing them to form a healthier, ‘basket weave’ pattern, which reduced stiffness – a key factor in tears and discomfort.

The authors also found that after transplantation, the scars expressed 719 genes differently to before. Genes that promote cell and blood vessel growth were expressed more, while genes that promote scar-forming processes were expressed less.

Underling mechanism still unknown

It is not known how exactly the transplants brought about the change. Having of a hair follicle in the scar was cosmetically acceptable for the participants as the scars were on the scalp. The researchers are now working to uncover the underlying mechanisms so they can develop therapies that remodel scar tissue towards healthy skin, without the hair follicle transplant. They can then test their findings on non-hairy skin, or on organs like the heart, which can suffer scarring after heart attacks, and the liver, which can suffer scarring through fatty liver disease and cirrhosis.

Dr Higgins said: “This work has obvious applications in restoring people’s confidence, but our approach goes beyond the cosmetic as scar tissue can cause problems in all our organs.

“While current treatments for scars like growth factors focus on single contributors to scarring, our new approach tackles multiple aspects, as the hair follicle likely delivers multiple growth factors all at once that remodel scar tissue. This lends further support to the use of treatments like hair transplantation that alter the very architecture and genetic expression of scars to restore function.”

Source: Imperial College London

For Acne Scars in Dark Skin, Microneedling Beats Chemical Peels

Chemical peels are a common treatment for acne scars, but a study published in the Journal of Clinical and Aesthetic Dermatology finds that, for patients with dark skin, microneedling is a significantly more effective treatment.

Researchers randomly assigned 60 patients with acne scars and dark skin (Fitzpatrick Skin Phototype IV to VI) to treatment with either 35% glycolic acid chemical peels or microneedling, both administered every two weeks for 12 weeks.

Microneedling therapy is a controlled skin injury that utilises instruments containing rows of thin needles that penetrate the dermis to a uniform depth. This induces rapidly-healing micropunctures with subsequent stimulation of collagen and elastin fibre production, resulting in skin remodelling.

Microneedling was initially developed as a tool for skin rejuvenation. However, it is now being used for a number of indications, which include: various forms of scars, alopecias, drug delivery, hyperhidrosis, stretch marks, and more. It is occasionally combined with delivery of radiofrequency energy, which is thought to enhance dermal remodelling and clinical effects. Despite its widespread use, data on the efficacy of microneedling are lacking.

Chemical peels involve applying a solution to the skin that removes the top layers.

Treatment produced an improvement of two points or more on the Goodman and Baron Scarring Grading System in 33% of patients who received chemical peels and 73% of patients who underwent microneedling.

“Based on the results of this study, patients whose darker skin precludes the use of stronger chemical peels, which can permanently discolour darker skin, should treat acne scars with microneedling,” said the study’s senior author Babar Rao, a professor of dermatology and pathology at Robert Wood Johnson Medical School. “For patients with lighter skin who can use stronger peels without risk of discoloration, chemical peels might still be the best option for some.”

Source: EurekAlert!

New Wound Dressing Minimises Scarring

Photo by Diana Polekhina on Unsplash
Photo by Diana Polekhina on Unsplash

A new wound dressing technology that can stop bleeding while preventing infection and scarring using a single material, has been developed. This technology also has potential applications in drug delivery, among other areas.

“Scarring is one of the worst consequences of severe wounds,” said Xiaoyang Wu, an associate professor in the Ben May Department of Cancer Research at the University of Chicago, noting that scar tissue formation is particularly common in human skin.

The researchers used a material science approach to develop a new method to overcome scarring, by impeding collagen synthesis by blocking transforming growth factor beta (TGF-β) – a cytokine that plays an important role in cell signaling, both in skin wound repair and tissue fibrosis.

“Increasing evidence suggests TGF-β is important in early phase wound repair for wound closure. But, later on, the signal may promote and enhance scarring,” Prof Wu said. This makes timing crucial. “We cannot simply block the signal, because that would slow down wound healing and would be dangerous for the patient,” he explained.

To get around this, the researchers came up with a delayed-release system combining a sutureless wound closure hydrogel material with a biodegradable microcapsule system, enabling them to control the release of the TGF-β inhibitor. “In this way, we can enhance skin wound repair and after 7-14 days can release the inhibitor that blocks the skin scarring process at the same time by using one material,” Prof Wu added.

The study results were recently published in Nature Communications.

At present, treatment of scarring is not ideal with little besides cosmetic surgery, and little can be done to prevent scar formation if a patient experiences a deep or messy wound. “The system we developed is very convenient for application,” said Wu, adding that the system has many possible future applications, such as drug delivery.

“We believe the novel system will have potential clinical importance in the future,” he said. To this end, the next steps include filing an investigational new drug (IND) application with the US Food and Drug Administration (FDA). Consistent manufacturing of the material is necessary and the researchers are exploring collaborations with pharmaceutical companies to move the research forward.

Since the system is a biocompatible material with adhesive properties, Wu said it has internal applications as well, adhering to and closing bleeding arteries and cardiac walls after irradiation with UV light. This was demonstrated in animal models, suggesting significant advantages as a traumatic wound sealant.

“Normal wound binding material does work well,” said Wu, noting that fibres are the most reliable material currently available, which, like surgical glue, is less biocompatible. “Biocompatibility is a significant advantage of our system,” he explained, “It is superior compared to current existing materials.”

Source: University of Chicago