Category: 8. Health

Pre-diabetes in younger individuals

These celebrities’ stories highlight the importance of awareness, education, and lifestyle changes in managing pre-diabetes. In an interview with HT Lifestyle, Dr Suchismitha Rajamanya, lead consultant and HOD, internal medicine, Aster Whitefield Hospital, Bengaluru, highlighted how pre-diabetes in younger Indians is an increasingly concerning issue.

She said, “Pre-diabetes, a state where blood sugar levels are higher than normal without yet being classified as type 2 diabetes, is an increasingly common diagnosis in younger people in their 20s and 30s in India. As we are seeing, pre-diabetes is on the rise due to sedentary lifestyles, irregular eating habits, stress levels and poor sleep patterns — all behaviours young people subscribe to in urban areas today.”

She added, “Prediabetes isn’t a diagnosis it’s a warning signal. If you make the right changes keep a healthy diet, exercise regularly, manage stress, and get the HbA1c test every year you may be able to completely reverse the risk factor. The trick is early detection. With increasing rates of type 2 diabetes in India, particularly in younger adults, pre-diabetes screening is not an option anymore; it is a necessity.”

What is pre-diabetes and why is it dangerous?

According to Dr Rajamanya, pre-diabetes is difficult to detect due to the absence of recognised symptoms. “You may feel perfectly well and full of energy, but your body’s management of blood levels may already be affecting your health. If no action is taken, a typical person will develop diabetes within 5-10 years and in some circumstances, less. The recent Indian Council of Medical Research (ICMR)-INDIAB study found that 15.3 percent of Indians have pre-diabetes many of which are unaware. Most concerning is that this is increasingly affecting the younger generation.”

Why you should care about the HbA1c test

Dr Rajamanya said an HbA1c (glycated hemoglobin) test is a very simple blood test. “It provides you with an alternative way of computing your average blood sugars from the last 2 to 3 months. Although a fasting sugar test would have only assessed your blood sugar at that moment, an HbA1c gives you a better snapshot of your blood sugars over a lengthier period of time. It is a great way to investigate your blood sugar levels before you enter the pre-diabetic stage when you might have the option to make lifestyle changes that could potentially reverse your diagnosis completely,” she explained.

Per the American Diabetes Association, Dr Rajamanya shared HbA1c results are used to determine:

⦿ Under 5.7 percent – normal

⦿ 5.7 percent to 6.4 percent – pre-diabetes

⦿ 6.5 percent and over – diabetes

“If you are a younger person having a family history of diabetes, or high BMI, or PCOS for women, or any metabolic disease history or problems, it is good practice to have an annual HbA1c test as a preventative measure,” she added.

Why are young Indians at risk?

According to Dr Rajamanya, these factors play a role:

1. Carbohydrate-heavy diet + long sitting breaks: Most of the Indian diet of refined carbohydrates and sugars can result in some younger adults who have long desk hours with hardly any movement.

2. Stress metabolic effects + sleep deprivation: Chronic stress and irregular sleep have metabolic effects, causing hormonal imbalance in the body, which can negatively impact insulin sensitivity.

3. Failure to have health appointments: Many individuals under the age of 35 are not routinely screened unless symptoms appear- and by that time the damage potentially has commenced.

Signs you should not ignore

While there are no definitive symptoms of pre-diabetes, as per Dr Rajamanya, common signs include the following, and it is advisable to visit your physician and get tested for these signs:

⦿ Unexplained fatigue

⦿ Excessively thirsty or urinating excessively

⦿ Unexplained changes in weight

⦿ Dark patches of skin on the neck or armpits- acanthosis nigricans

⦿ Recurrent infections or wounds that take longer to heal

Note to readers: This article is for informational purposes only and not a substitute for professional medical advice. Always seek the advice of your doctor with any questions about a medical condition.

On one of the most memorable days of my life, I walked into a doctor’s office with an incipient migraine and walked out half an hour later pain-free. It was the early ’90s, and I’d been suffering from the headaches—often accompanied by nausea and vomiting, occasionally somewhat eased by ibuprofen—since the age of 14. I can’t recall why on that day I decided to request an appointment, but I can still see the doctor fumbling with the wrapping of a cartridge encasing a hypodermic needle filled with a new drug. She got migraines, too, she’d told me, so when she placed the cartridge on my arm and pressed the button delivering the shot, we both exhibited the curious anticipation of experimenters, wondering if something miraculous was in the offing.

It was. Within five minutes, the nagging throb that had bloomed on my right temple a few hours earlier had vanished. That made us both giddy. Whether the new drug, sumatriptan (marketed as Imitrex), also worked for that doctor, I’ll never know. But I was lucky. Over the decades that followed, sumatriptan has reliably tamed the migraines that have intermittently plagued me, rescuing me from countless hours of misery. Whenever anyone complains about Big Pharma or fantasizes about having been born in an earlier era, my ironclad response is that I can’t imagine my life without sumatriptan—or, rather, I can, and the thought is chilling.

I’m lucky. As the journalist Tom Zeller Jr. recounts in his illuminating new book, The Headache, people with migraines or cluster headaches (Zeller’s own affliction) often find that recommended treatments either don’t work or decline in effectiveness over the course of months. Cluster headaches, like migraines, are called “primary headaches,” Zeller explains, “meaning the head pain and accompanying battery of other neurological effects constitute disorders unto themselves, rather than symptoms of some other underlying disease.” Even the fairly common migraine is poorly understood by those who don’t get them. I once worked with a colleague who was convinced I was being careless with my health because I didn’t regard my headaches as symptoms of some grave condition that could, and ought, to be cured.

By Tom Zeller Jr. Mariner Books.

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The Headache is an account of what we have learned about migraine and cluster headaches (less than you’d think) and the state of research developing treatments. The newest of those treatments are blockers that inhibit the uptake of calcitonin gene-related peptide, CGRP, a “key chemical messenger in the nervous system’s pain communication pathway,” according to Zeller. Researchers knew that CGRP could induce migraines in experimental subjects (all praise the sacrifices of those heroes!), and this new class of drugs binds to the chemical to prevent it from binding to neural receptors.

Cluster headaches are relatively rare, but migraines are not, and one study calculated the cost to the U.S. economy of migraines alone is as much as $1 trillion. Yet research into the causes and cures for primary headaches has been sluggish, for reasons that are highly contested. While the medical explanations in The Headache occasionally made my eyes glaze over, Zeller’s accounts of feuds among headache researchers and their combined wrath at what they insist is inadequate National Institutes of Health funding for their work offers a delectable blend of dish and substance. When one scientist likened migraine research to a massive Airbus plane requiring four fully fueled engines to get it off the ground, Zeller asked him what, exactly, was keeping the plane on the tarmac. “Too many female passengers,” was the reply.

Female migraineurs outnumber their male counterparts by 3 to 1, while the gender breakdown is reversed for cluster headaches. Many headache experts believe that this explains why migraine isn’t taken seriously by the medical establishment, whose tendency to dismiss pain in female patients has been well documented. Zeller observes that cluster headache sufferers, by contrast, tend to hide their condition, something he himself did during an early stint at the New York Times. The Headache includes the story of an air traffic controller who concealed his cluster headaches for three decades, knowing that the condition would trigger an automatic medical disqualification from a job he loved. He resorted to keeping his medications (which did not impair his performance) secret and ducking out of work during an episode to inhale oxygen from a tank he kept in his car.

For Zeller’s part, he found it difficult to admit how debilitated he was by a disorder that many people conflate with the discomfort caused by a hangover. Cluster headaches, however, are often ranked among the worst pain a human can experience. While migraineurs tend to retreat to dark quiet rooms to wait out their affliction, people with cluster headaches are restless, often pacing, rocking, and pounding their heads. While cluster headaches don’t last all day like a migraine, they can recur every day or multiple times per day within the window of a period that can last weeks or months, followed by a period of remission. In The Headache, Zeller relates the story of a young man whose cluster headaches proved so relentless and tormenting that he took his own life, grimly confirming the disorder’s nickname: suicide headaches. Zeller himself recounts a period when, while working on a demanding story, he experienced a cluster attack and resorted to “medicating myself with absurd tides of chemical experimentation and excess,” ranging from caffeine, steroids, and magnesium to a CGRP blocker called verapamil—a drug on which he overdosed, passing out.

Though we have different kinds of headaches, there’s much that’s familiar to me in Zeller’s account. I, too, have found it difficult to convey just how disabling a mere headache can be. And I certainly recognized Zeller’s almost superstitious hoarding of medication doses, splitting them to stretch the supply, and the way Zeller would “jealously count those blue injections like a Scrooge, worrying over their limited number, wondering whether they’d last.” These drugs are the treasure we require to placate an angry god. Insurance companies can be stingy with the number of doses they allow per month, so it’s imperative to keep renewing the prescription regularly, even in the absence of headaches, so that you hit any future bad period with an ample supply. The fear of running out is petrifying—although, thankfully, well in the past for me now that sumatriptan has gone generic and can be bought online. The more recently developed CGRP blockers, however, can be brutally expensive. And most primary headache medications only work for half the people who try them, and then often only half the time.

Maddeningly, scientists still can’t say what causes primary headaches. Fierce debate rages among them over whether these are disorders of the vascular system—dilated blood vessels pressing against nerves—or of the central nervous system, arising from some dysfunction in the brain. The hypothalamus, which regulates the autonomic nervous system, seems implicated in cluster headaches, with their mysterious link to the body’s circadian rhythms. Migraines vary widely from person to person, but also in the same person during the course of a lifetime. My migraines once were synced to hormonal cycles. Now they only come at night, and especially when it rains or the humidity tops 75 percent. Or when my blood sugar gets too low. Or when I drink wine. I never experienced migraine aura—a disturbance in vision—until about 15 years ago. Now, my eyesight will occasionally be marred by a crescent of shimmering silver triangles (a classic migraine aura), but with no subsequent headache attached.

No wonder headache scientists are stumped, although several of the sources Zeller spoke with also complained that the stigma attached to primary headaches as an “unserious” medical condition has kept gifted researchers away from the field. Former NIH director Story Landis told Zeller that the agency—which has demonstrably underfunded headache research relative to the impact primary headaches have on society—simply didn’t get enough high-quality grant proposals in the area. Landis suggested, Zeller writes, “that headache researchers had been poorly conditioned by industry to focus on pills and shots, rather than foundational science,” such as identifying the cause or causes of the disorders. But if Big Pharma is the only source of funding for headache research, who can blame them?

When an advocate for headache sufferers asked Zeller what he’d learned in all his admirably extensive research for The Headache, the author found himself stammering and backtracking, qualifying his own suffering as not “the worst of what cluster headaches can inflict on a person,” adding that “there are bigger problems.” Then he pulled up. For millions of people of all races and genders—including Zeller himself!—primary headaches are a literal torment. Though I seldom endure that myself now, I remember all too well what a full-blown migraine was like. “It’s not just a headache” is the answer Zeller finally comes up with, and on that we should all agree.

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Pfizer’s Covid vaccine for young children may not be renewed by the US Food and Drug Administration (FDA) this fall, prompting Moderna to fill possible gaps in supply, according to an email obtained by the Guardian.

The move would pull the only remaining Covid vaccine for all children under five from the market.

The Moderna vaccine is only approved for children with one or more health conditions, and the pediatric Covid vaccine from Novavax is only available for children aged 12 and up with health conditions.

“It certainly would create a hole in the availability of vaccines,” said Georges Benjamin, executive director of the American Public Health Association.

“And to do it this late in the season – I think clearly it’s inappropriate.”

According to an email from the National Center for Immunization and Respiratory Diseases (NCIRD), Pfizer said the FDA recently informed the pharmaceutical company that it may not renew the emergency use authorization for its pediatric Covid vaccine for the 2025 respiratory season.

The email was sent on Friday to state and local vaccination grantees.

The Pfizer vaccine is given to children between the ages of six months and four years.

Pfizer expects its Covid vaccine for children aged five to 11 to be fully licensed this fall, the email said.

The Centers for Disease Control and Prevention (CDC) is “in discussions” with Moderna about rapidly increasing its Covid vaccine supply for young children, according to the email.

That includes internal planning about volume, timing, and potential supply gaps.

“We are working to ensure there will be sufficient supply,” said Chris Ridley, a Moderna spokesperson.

The CDC, the US Department for Health and Human Services (HHS), and Pfizer did not respond to media inquiries by publication time.

In July, Moderna received FDA approval of its Covid pediatric shot. But the vaccine was only approved for children with one or more health conditions that make them more vulnerable to Covid. This move could limit access to Covid vaccines.

“We already have a low number of people using the vaccines to start with,” Benjamin said.

“There hasn’t been enough promotion of vaccinations for kids, and then you have Mr [Robert F] Kennedy’s [Jr] unscientific statements about the safety and efficacy of vaccines, particularly Covid vaccines, for both pregnant women and kids. It has muddied the waters of what people know about the safety and efficacy of the vaccine.”

The vaccine is extremely effective, especially against hospitalization and death.

Yet only 5.6% of children aged six months to four years are vaccinated against Covid, and about 15% of children aged five to 17 are vaccinated, according to the CDC.

While older adults have the highest rates of hospitalization and death, children continue seeing hospitalization rates from Covid similar to rates in 2020 and 2021.

And there are other concerns with Covid infection.

“We don’t know the long-term impact for kids who have gotten Covid as a disease. We do know it does cause a multi-systemic inflammatory process in a number of kids, which is very severe, and we don’t know the long-term implications for long Covid in kids,” Benjamin said.

Covid cases are rising in many parts of the US amid other vaccine restrictions proposed and implemented by health officials.

I look like I’m about 28. Or maybe 38.

That’s according to Harvard’s “FaceAge” algorithm, which uses photos to determine a person’s supposed biological age — meant as a quick proxy for wellness.

This app is one of several new efforts to turn selfies into diagnostic tools.

There’s one for diagnosing nasal congestion, another for seasonal allergies, and a few safe driving apps that watch your face for signs of drowsiness. Some face scanners measure pain, illness, or signs of autism. One aims to track PTSD in kids to spare them from having to talk about traumatic issues over and over again.

Since 2022, facial recognition for the clinic has blossomed, alongside rapid advancements in artificial intelligence and chipmaking. This year, new face technologies promising to diagnose diseases earlier, treat patients better, and ostensibly predict early death are taking off.

“It’s a medical biomarker, not just a gimmick,” said FaceAge creator and radiologist Dr. Raymond Mak, who’s leading the team at Harvard Medical School developing facial recognition technology that Business Insider recently tested.

Ethics experts worry about what we’re barreling into, without better understanding exactly what this tech is measuring, or why.

“AI is entering these spaces fast,” Malihe Alikhani, an assistant professor of machine learning at Northeastern University, told Business Insider. “It’s about making sure that it is safe and beneficial.”

Your face is a reflection of your health

Our faces say a lot about our physical, mental, and biological health. While this is new territory for computers, humans have read faces to make quick judgments for thousands of years.

Research suggests we developed a third type of cone in our eyeballs about 30 million years ago, specifically to scan each other’s faces for signs of health or sickness. That cone allows us to read faces in shades of red and green.

“People look at rosy cheeks and they see that as a sign of health. When we want to draw a face that’s sick, we’d make it green,” Professor Brad Duchaine, a neuroscientist who studies facial perception at Dartmouth, told Business Insider.

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Business Insider tells the innovative stories you want to know

It’s true: A flush can indicate good blood flow, or high levels of carotenoids in the skin from fruits and veggies we eat.

Dr. Bahman Guyuron, a plastic surgeon in Cleveland, studied identical twins with different lifestyles to see how factors like smoking and stress impact their faces.

Consistently, the twin with more stress and more toxins in their bodies looked several years older. Sagging skin and wrinkles can reflect poorer internal health, with lower collagen production and higher levels of stress hormones.

Conversely, studies show that superaging centenarians — whose organs and cells are working unbelievably efficiently — look, on average, about 27 years younger than they are.

I tried a face scanning app

One of the first medical applications of face-reading tech was Face2Gene, an app first released in 2014 that helps doctors diagnose genetic conditions. Studies suggest Face2Gene is better than human doctors at extracting information from a person’s face and then linking those features to a specific genetic issue.

The Australian app PainChek has tracked the pain of nursing home patients since 2017. It is mostly used for dementia patients who may not be able to verbalize pain. In a recent announcement, the company said it is awaiting FDA approval and could be cleared by September 2025.

I wanted to try one of these apps for myself. Since I write a lot about aging, I decided to try FaceAge, Harvard’s new app that ostensibly measures your biological age. It is not yet available for public use; it is being used as a research tool for now. The ultimate goal, researchers say, would be to use selfies to do better diagnostic work. FaceAge could one day improve cancer treatments by tailoring them to a patient’s unique biology and health status, or maybe even help flag other health issues before they happen.

The FaceAge algorithm pays attention to two main areas of the face: the nasal labial folds, from the nose to the lips, and the temples between the eyes and ears.

The idea is to spot premature or accelerated signs of aging that could be a red flag for internal problems. “If your face age is accelerating quicker than your chronological age, it’s a very poor prognostic sign,” Mak, one of the developers behind FaceAge, told Business Insider.

I submitted four photos to the app.

In the darkest, blurriest photo I provided, the app thought I was 27.9 years old — a little more than a decade below my actual age.

The picture I took with no makeup on, and my face thrust out into the bright mid-day sunshine, gave me the oldest FaceAge, even though all of these pictures were taken within the past year.

One selfie taken in the dark of winter and another on a cloudy day ended up somewhere in the middle, making me look young-ish.

Humans (and face-scanning apps) use the proliferation of lines, sharp edges, and more details to assess someone’s age. That’s why people look younger in blurry photos — or with surgery or makeup to smooth over their wrinkles.

In “a really, really, really blurry photograph of a face, what you’ve done is you’ve stripped out all of the high spatial frequency information,” neuroscientist Bevil Conway, a senior investigator at the National Institutes of Health, told Business Insider.

Direct light, like a ring light, can help mask old age. The midday sun, coming down on my face from above, had the opposite effect.

So, what did I learn from my experiment? FaceAge told me I’m looking great (and young!) and should keep up my healthy habits. Still, its assessments were all over the place. Face Age is confident each time you run it, but that confidence masks the fact that it can’t really tell how well I’m aging over time.

Is my body 10 years younger than me, or just one? While I do eat a relatively healthy diet and exercise regularly, I’m curious how much the differences in lighting affected my results.

The ethics are blurry

Even if it’s something as seemingly innocuous as measuring your age, bringing AI into the doctor’s office is fraught with ethical conundrums.

“We have been through a few years now of companies coming up with these systems, selling them to hospitals, selling them to doctors, selling them to border protection, and then after a while they’re like, ‘oops,’” Alikhani, the AI ethics expert, said.

Readers may remember the uproar over the highly controversial Stanford study that developed “gaydar” AI in 2017. The app purported to spot someone’s sexual orientation. Critics said it was just picking up on social and environmental cues that had nothing to do with sexuality, like makeup, facial hair, and sun exposure.

Another team of researchers from Shanghai Jiao Tong University developed an algorithm that promised to identify criminals and terrorists, or people with law-breaking tendencies.

These efforts feel uncomfortably close to the pseudoscientific practice of physiognomy, a deeply flawed practice that’s been used for centuries to justify racism and bigotry, Alikhani said. Facial expression is highly context-dependent, varying not only based on a person’s gender and culture, but also by the individual and the moment, she said.

“Better healthcare involves patients more in the decision-making,” Alikhani said. “What are we doing if we’re putting that in the hands of AI?”

If the thought of pumping iron or holding a plank doesn’t put a spring in your step, maybe the latest exercise trend to dominate social media will: Japanese interval walking.

The idea is simple: alternate between three minutes of fast and three minutes of slow walking, ideally for 30 minutes at a time.

“The fast walking pace is typically fast [enough] that you are not able to speak in long sentences,” said Dr Kristian Karstoft, an associate professor at the University of Copenhagen, who has studied the method. “And then the slow intervals are so slow that you are able to recover.” He added that people could often find it challenging to walk slowly enough during these intervals.

Putting the approach to the test, I hit the area around King’s Cross in central London.

I began striding out, as though late for a train. Three minutes later my watch beeped and I slowed down, pottering along as if searching for a dropped earring. Another beep and I sped up once more, arms swinging.

I was slightly worried what passersby might think of my erratic pace – I suspect I looked as if I needed the loo but dared not risk a jog. Already I was regretting attempting this without my two flat-coated retrievers: if they were in tow I could at least have blamed my dawdling intervals on their lamp-post sniffing.

After 30 minutes I felt warm, but not exactly out of puff.

Karstoft said the approach was particularly suited to people prone to running injuries, as walking is less hard on the joints, or middle-aged or older adults who do not do much regular training. People who were already pretty fit, he said, would need to jog or run for intervals to experience similar benefits.

The regime is similar to high-intensity interval training (Hiit). Dr Shaun Phillips, a senior lecturer in sport and exercise physiology at the University of Edinburgh, said: “High-intensity exercise can give similar benefits to moderate-intensity exercise but in a shorter time frame [or] with a lower volume of exercise. The use of high-intensity places a bigger stimulus on the body to adapt.”

But not everyone can keep up a furious pace, even when walking. Phillips said people who were less active or fit should start with normal walking to get into the swing of it, and then try interval walking.

“A way to maximise your ability to do high-intensity training is to do it with the alternating intensities, meaning the interval-based training,” Karstoft said.

While high-intensity interval walking has recently become popular on TikTok, where enthusiasts share videos of themselves earnestly striding around town parks, the idea goes back more than 20 years when scientists in Japan began studying it in middle-aged and older adults.

According to one Japanese study, involving an analysis of data from 139 healthy participants with an average age of 63, people who did high-intensity interval walking on four or more days a week over a five-month period increased their peak aerobic capacity, indicating an improvement in physical fitness. What’s more, these improvements were greater than for participants who had undertaken a walking regime of continuous, moderate intensity or who did no walking training.

The study also suggested high-intensity interval walking may reduce blood pressure and increase the strength of the knee joint.

A small randomised control trial by Karstoft and his colleagues found the approach could also benefit people with type 2 diabetes, including by improving their glycaemic control.

Four months of high-intensity interval walking was associated with greater benefits than continuous walking, even though the overall energy expenditure and mean training intensity were the same.

“Typically with interval walking, we’ve seen a gain in fitness level of around 15% to 20% compared to trivial or no improvements in fitness levels when subjects are doing the continuous walking [or no walking],” Karstoft said. “We’ve seen improvements in body composition with an average weight loss during four to six months of training of around three to five kilograms, mainly due to fat mass.”

A review on the topic published by Karstoft and his colleagues last year concluded that Japanese interval walking was a feasible and effective training regimen for older, fragile people. “It significantly enhances fitness, muscle strength, and health markers,” they wrote.

But, Phillips acknowledged, while some people like the challenge of higher intensity periods of exercise, others hate it.

“We’re certainly never going to come to the ideal exercise protocol that everybody loves,” he said. “It’s about trying to give as many workable and beneficial options as possible that people can pick from.”

Introduction

Diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels.^1–3 When blood glucose is not effectively controlled for a long period, it can lead to a variety of complications, among which DFU is one of the serious and common complications.^4–6 Hyperglycemia contributes to DFUs through several mechanisms: first, long-term hyperglycemia induces neuropathy, leading to loss of protective sensation in the foot, making patients insensitive to trauma or pressure, and thus susceptible to foot injuries; second, hyperglycemia also leads to vasculopathy, which reduces the blood supply to the foot and affects wound healing. In addition, hyperglycemia also weakens immune function and increases the risk of infection, further aggravating ulcer formation and development.^7–9 These factors work together to greatly affect the quality of life of patients. About 6.3% of the world’s diabetic population suffers from DFU, and more than half of all diabetic patients are at risk of DFU. According to statistics, the global healthcare expenditure on DFU treatment reaches up to $40 billion per year, putting enormous economic pressure on national healthcare systems.^10,11 Currently, the treatment of DFU relies on traditional approaches such as glycemic control, anti-infective therapy, topical care, and surgery.^12,13 However, these treatment modalities often have limited effectiveness, and there is an urgent need to develop and explore safe and effective therapeutic strategies.

Table 1 The Mechanism of Action and Experimental Model of Mesenchymal Stem Cell Exosomes in the Treatment of Diabetic Foot Ulcers

Table 2 Case Studies of Stem Cell Exosomes from Different Sources in the Treatment of Diabetic Foot Ulcers

MSC treatment of DFU has achieved significant results in preclinical studies and clinical trials, but has not been widely used in routine clinical treatment.^14–16 Numerous studies have shown that stem cells promote the healing process of DFU through multiple mechanisms, including promoting wound healing, enhancing angiogenesis, and inhibiting inflammation.^17,18 However, the exact mechanism of stem cell therapy for DFU has not been fully clarified. It has been found that the therapeutic effect of stem cells is not only through their differentiation potential but also through their paracrine effects. Paracrine action refers to the secretion of bioactive factors by stem cells, such as cytokines, microRNA exosomes, etc. These released substances can promote tissue repair and regeneration by regulating the local microenvironment.^19–21 Among the substances released by stem cells, exosomes, as a key component, play an important role in promoting cell migration, proliferation, and differentiation.²²

In recent years, Mesenchymal Stem Cell-derived Exosomes (MSC-Exos) have become an important research direction for DFU therapy due to their great potential in tissue repair and regeneration.^23–25 It has been shown that exosomes deliver biological signals and regulate cellular functions through interactions with target cells, which in turn promote wound healing.^26–28 Therefore, MSC-Exos is considered a promising treatment for DFU.

This review focuses on the role and mechanism of exosomes from different sources of stem cells in improving diabetic wound healing and enhancing the effectiveness of stem cell exosomes in treating DFUs from the perspective of tissue engineering to provide more promising candidates and ideas for the treatment of diabetic wound healing.

Biological Properties of Stem Cell Exosomes

Sources and Mechanisms of Secretion

Exosomes are nanovesicles with a diameter of about 30–150 nm.^29–31 It was first discovered in 1983 when Harding et al³² were studying erythrocytes and stumbled upon the discovery that the cells secreted tiny vesicles, which were not simply cellular waste products, but were formed by periplasmic ectasia and had specific biological functions. It was not until 1996 that the concept of exosomes was widely recognized and clarified by the scientific community. Exosomes contain many biologically active substances, such as proteins, RNA, lipids, etc, which can regulate target cells through intercellular transduction.^33,34 In addition, a distinctive feature of stem cell exosomes is their ability to carry biomolecules from source stem cells and deliver these substances to target cells, thus exerting a variety of biological effects, such as promoting tissue repair, anti-inflammation, and immune modulation.³⁵ The formation of exosomes begins with the endocytosis of cell membranes to form endosomes, which contain many extracellular substances inside. During maturation, endosomes are transformed into multivesicular bodies, in which small endosomes are encapsulated within large vesicles. The multivesicular body has multiple small vesicle-like vesicles, which contain many exosomes that will be secreted. When the multivesicular body matures, it fuses with the cell membrane and releases the inner vesicles outside the cell, ie, exosomes^36–39 (see Figure 1). After formation, exosomes can be taken up by target cells and can participate in intercellular communication through receptor-ligand interaction, direct membrane fusion, and endocytosis.⁴⁰

Figure 1 Biogenesis of exosomes.

In characterizing and analyzing MSC-Exos, we usually use the following techniques: transmission electron microscopy (TEM) for observing the morphological features of exosomes and confirming their typical cup structure; nanoparticle tracking analysis (NTA) for determining the size distribution and concentration of exosomes; and protein blotting (Western blotting) for confirming the identity and purity of exosome-specific proteins by identifying them to confirm their identity and purity.^41,42

Biological Functions

Stem cell exosomes are involved in intercellular communication and signaling regulation.⁴³ Stem cell exosomes can regulate the function of target cells by carrying bioinformatic substances that transmit information between cells. They also selectively deliver signaling molecules to target cells by binding to specific receptors.^44,45 In addition, RNA molecules in exosomes can be transcribed and expressed in target cells, thereby altering cellular biological behaviors such as proliferation, migration, and differentiation.^20,46,47 Stem cell exosomes can also promote tissue repair and regeneration.^22,48,49 They can promote cell proliferation, migration, and tissue repair, especially in the healing process of chronic wounds such as diabetic wounds. Secondly, stem cell exosomes promote neoangiogenesis and improve the repair and regeneration of ischemic tissues by regulating endothelial cell proliferation, migration, and lumen formation.^50–52 In addition, stem cell exosomes have anti-inflammatory effects, which can reduce the local inflammatory response, regulate the function of immune cells, inhibit the secretion of pro-inflammatory cytokines, and avoid excessive inflammatory response at the wound.^53,54 In addition, engineered stem cell exosomes can be used for drug delivery and gene therapy.^55,56 Exosomes can carry small-molecule drugs, and their natural biocompatibility and targeting properties make them ideal drug carriers. In addition, stem cell exosomes repair or replace specific genes by loading molecules such as mRNA, siRNA, shRNA, etc, to treat diseases associated with genetic defects.⁵⁷ In addition, stem cell exosomes have antioxidant effects.⁵⁸ Exosomes released from stem cells are enriched with a variety of antioxidant enzymes, including superoxide dismutase, catalase, etc, which can scavenge reactive oxygen species, thus reducing cellular damage caused by oxidative stress.^59,60

Mechanisms of Stem Cell Exosomes in the Treatment of Diabetic Foot Wounds

Inflammation Regulation

Excessive inflammatory response of the wound is a major cause of DFU, and abnormal macrophage polarization and cytokine overexpression can lead to a persistent inflammatory state of the wound and may also trigger secondary peripheral tissue injury.^8,61 Therefore, regulation of wound inflammation is one of the important targets for DFU therapy. In recent years, more and more studies have proven that many MSC-Exos can reduce the inflammatory response and promote wound healing^62,63 MSC-Exos as a potential therapeutic tool provides new hope for the clinical treatment of DFU.

Inhibition of Inflammatory Factors

MSC-Exos can regulate the expression of inflammatory factors by modulating the local immune response of the wound, thus inhibiting excessive inflammatory response. Yan et al⁶⁴ showed that under hyperglycemic conditions, exosomes released from human umbilical cord mesenchymal stem cells significantly reduced the expression of inflammatory factors such as IL-6, 1L-1β, and TNF-α, thus avoiding excessive inflammatory response. In addition, Wang et al⁶⁵ found that adipocyte-derived MSC-Exos could attenuate the inflammatory response by inhibiting the release of IL-27. Taken together, these studies suggest that exosomes isolated from multiple stem cell types can promote wound healing by regulating inflammatory mediators that play a key role in different stages of wound healing.

Macrophage Polarization Induction

MSC-Exos also regulates the phagocyte polarization state and promotes the conversion of M1-type macrophages to M2-type. Macrophages consist of two polarization states, M1 macrophages and M2 macrophages.⁶⁶ M1 macrophages are generally found in the early stage of the inflammatory response and play a pro-inflammatory role.⁶⁷ M2 macrophages, on the other hand, are generally found in the later stages of the inflammatory response and play an anti-inflammatory and pro-wound healing role.⁶⁷ However, in DFU wounds, hyperglycemia continues to stimulate macrophages to secrete large amounts of pro-inflammatory factors, which leads to the persistence of the M1 phenotype in macrophages at the site of rupture, preventing further wound healing.^68,69 Therefore, promoting the conversion of M1-type macrophages to M2-type may be an effective option for the treatment of DFU wounds.

Zhu et al⁷⁰ showed that adipose-derived MSC-Exos polarized macrophages to the M2 phenotype, which enhanced angiogenesis. He et al⁷¹ showed that bone marrow-derived MSC-Exos induced macrophage conversion to the M2 phenotype, attenuated inflammation, and promoted wound healing by targeting the PKNOX1 gene via transporter miR-223. Chamberlain et al⁷² found that bone marrow-derived MSC-Exos promoted macrophage conversion to M2 type and exerted inflammation modulation and accelerated tendon healing in a mouse tendon injury model. In addition, Li et al⁷³ showed that adipose-derived MSC-Exos inhibited the macrophage migration inhibitory factor, MIF, and promoted the conversion of M1-type macrophages to M2-type macrophages via miR-451a. Thus, MSC-Exos plays an important immunomodulatory role in diabetic wound healing by regulating the polarization state of macrophages and promoting the conversion of M1-type macrophages to M2-type.

Oxidative Stress Regulation

MSC-Exos reduces oxidative stress, relieves wound inflammation, and accelerates the healing process. Yan et al⁶⁴ showed that human umbilical cord-derived MSC-Exos inhibits the expression of two proteins, NOX1 and NOX, in human umbilical vein endothelial cells, which reduces oxidative stress. Xue et al⁷⁴ demonstrated that adipose-derived MSC-Exos promoted the expression of Nrf2 protein, which inhibited the expression of Nrf2 proteins in human keratinocytes, fibroblasts, and human umbilical vein endothelial cells, thereby reducing the expression of oxidative stress-related proteins and reducing oxidative stress. Zhang et al⁷⁵ showed that adipose-derived MSC-Exos could reduce ROS accumulation, attenuate oxidative stress induced by hyperglycemia, and mitigate inflammatory responses by modulating the SIRT3/SOD2 axis, thereby accelerating wound healing in a diabetes model. In addition, Ren et al⁷⁶ found that adipose-derived MSC-Exos could reduce oxidative stress by releasing eHSP90 protein, and it could lead to accelerated diabetic wound healing.

MSC-Exos has multiple mechanisms in the inflammatory regulation of DFU, including inflammatory factor inhibition, macrophage polarization induction, and oxidative stress regulation. Under the combined effect of these mechanisms, inflammatory overreaction can be avoided and wound healing can be promoted, as well as providing new ideas for the treatment of DFU.

Promote Cell Proliferation, Migration, and Angiogenesis

Promoting cell proliferation and migration, and angiogenesis is crucial in the comprehensive treatment of DFU wounds. Diabetic foot wounds are often associated with chronic inflammation, inadequate blood supply, and impaired cellular function; therefore, promoting the proliferation and migration of fibroblasts and other cells from diabetic patients can help accelerate the healing process.^77,78 Cell proliferation and migration can promote wound epithelialization, collagen synthesis, and tissue repair, and reduce wound exposure time, thus reducing the risk of infection and complications.^79,80 Meanwhile, angiogenesis is a key component in wound healing because DFU wounds often lack sufficient oxygen and nutrients due to impaired microcirculation.^81–83 Therefore, by promoting new angiogenesis, the local blood supply can be improved to provide the necessary nutrients and oxygen for wound repair, thus accelerating healing and reducing the risk of amputation.

Li et al⁸⁴ found that the proliferation and migration of fibroblasts play key roles in wound repair, and MSC-Exos plays a crucial role in stimulating these cellular activities. Li et al⁸⁵ observed by wound scratch assay that adipose-derived MSC-Exos could be taken up by fibroblasts and significantly promoted cell migration in a dose-dependent manner after internalization. Specifically, the migration rate of MSC-Exos-treated fibroblasts increased by approximately 40% (p < 0.01) after 24 hours compared with the control group, suggesting a significant promoting effect of MSC-Exos. In addition, MSC-Exos promoted collagen synthesis and upregulated related gene expression. In a mouse skin incision model, adipose-derived MSC-Exos could be recruited to the wound and significantly accelerated skin wound healing. Xue et al⁷⁴ reported that administration of adipose-derived MSC-Exos to a diabetic rat model resulted in increased levels of angiogenic and growth factor expression in wound beds, and led to a significant reduction in the size of foot wound ulcers in rats. Ma et al⁸⁶ showed that injection of adipose-derived MSC-Exos into rats with total skin defects was found to be taken up by fibroblasts and human umbilical vein endothelial cells, and could promote human venous endothelial cell production and fibroblast proliferation and migration.

Promoting Nerve Regeneration

Patients with diabetes are often associated with neuropathy.^87,88 Neuropathy may result in sensory loss and neuropathic pain, which together may lead to uneven loading of the foot, increased pressure, and subcutaneous edema, which can increase the risk of falls and foot ulcers⁸⁹ In addition, the nervous system plays an important role in DFU wound healing.⁹⁰ In the treatment of DFU wounds, the promotion of nerve regeneration may favor the healing of ulcer wounds.

Fan et al⁹¹ developed an engineered MSC-Exos carrying miR-146, which was administered systemically to a diabetic mouse model and found to be therapeutically effective for nerve restoration, with significant increases and decreases in nerve conduction velocities as well as thermal and mechanical stimulation thresholds, respectively. Nakano et al⁹² found that in vivo injection of bone marrow-derived MSC-Exos repaired damaged neurons and glial cells. In addition, Singh et al⁹³ reported that bone marrow-derived MSC-Exos was fused with polypyrrole nanoparticles containing liposomes, which were injected into the muscles of rats with a diabetic neuropathy model, and found that nerve conduction velocity and compound muscle action potentials were normalized in the injected rats. In addition, Wang et al⁹⁴ developed a miR-218-carrying adipose-derived MSC-Exos, and treatment utilizing miR-218-carrying MSC-Exos in combination with engineered scaffolds promotes the regeneration of sciatic nerves in a sciatic nerve injury model.

The nervous system is critical for DFU healing, and promoting nerve regeneration facilitates diabetic wound healing. As all of the above studies have demonstrated, engineered MSC-Exos carrying specific miRNAs or in combination with other materials can significantly promote nerve repair and functional recovery in diabetic model animals, providing a new strategy for DFU treatment.

Other

Accumulation of advanced glycosylation end products (AGEs) in DFUs triggers oxidative stress and inflammatory responses, inhibits cell proliferation and migration, and thus impedes diabetic wound healing.^95,96 Tang et al⁹⁷ treated rat chondrocytes with AGEs to induce cellular damage. Subsequent treatment of damaged chondrocytes with bone marrow-derived MSC-Exos revealed that their exosomes abrogated AGEs-mediated chondrocyte apoptosis. Therefore, treatment targeting AGEs is expected to promote wound repair and provide new ideas for DFU treatment. In addition, bacterial biofilms are widely present in DFUs, which are formed by the encapsulation of a polysaccharide matrix secreted by bacteria and are highly drug-resistant and immune-resistant, significantly increasing the difficulty of treatment. Bacteria in biofilms may release inflammatory factors that trigger chronic inflammation and inhibit cell proliferation and migration.^98,99 At the same time, the presence of biofilm may also exacerbate local hypoxia, further affecting tissue repair. Therefore, the elimination of bacterial biofilm is a key aspect of DFU treatment. Bakadia et al¹⁰⁰ developed a novel double cross-linked hydrogel based on silk proteins, which contains MSC-Exos, and used it to treat diabetic wounds, and found that biofilm at the wounds became thinner after treatment. In summary, stem cell-derived exosomes can act through multiple mechanisms and therapeutic targets when treating DFU wounds (see Table 1).

Stem Cell Exosomes from Different Sources for the Treatment of Diabetic Foot Wounds

Umbilical cord mesenchymal stem cell-derived exosomes, bone marrow mesenchymal stem cell-derived exosomes, and adipose-derived mesenchymal stem cell-derived exosomes have many similarities in the treatment of DFU wounds, but the mechanism of action, therapeutic efficacy, and characteristics of the exosomes differ due to their different sources.^101–104 For this reason, according to the pathophysiological characteristics of DFU wounds, the selection of MSC-Exos from different sources can better meet the therapeutic needs.

AD-MSCs Exosomes

AD-MSCs exosomes are derived from adipose tissue, can be isolated and cultured from adipose tissue, and have strong regenerative and repairing ability, which has specific advantages in improving the tissue repair of DFU wounds.¹⁰⁵ AD-MSCs’ exosomes have a wide range of clinical applications as a non-cellular therapy.

AD-MSCs’ exosomes can promote DFU wound healing through anti-inflammation. It inhibits the release of pro-inflammatory factors such as IL-6, TNF-α, and IL-1β in diabetic wounds.^74,106,107 In addition, AD-MSCs’ exosomes increase the release of anti-inflammatory cytokines such as IL-10.¹⁰⁸ AD-MSCs’ exosomes are also enriched with specific miRNAs to control inflammation. Waters et al¹⁰⁹ found that AD-MSCs’ exosomes enriched with miR-146a inhibited the NF-κB signaling pathway, thereby decreasing pro-inflammatory factor release. AD-MSCs’ exosomes induced macrophage M2 polarization. Jiang et al¹¹⁰ showed that microRNA (miR)-30d-5p-enriched AD-MSCs exosomes inhibited macrophage M1 polarization. Wang et al¹¹¹ injected diabetic mice with exosomes of AD-MSCs and found that these exosomes induced macrophage M1 polarization via the JAK/STAT6 signaling pathway. STAT6 signaling pathway induced macrophage M2 phenotypic polarization and induced M2 macrophage proliferation, migration, and adhesion, promoting angiogenesis and hemotransfusion in the ischemic lower limbs of type 2 diabetic mice. AD-MSCs’ exosomes also play an important role in regulating oxidative stress, as they can regulate reactive oxygen species (ROS) production and prevent excessive oxidative stress from stimulating wounds.^112–114 Zhang et al¹¹⁵ showed that adipose tissue-derived MSC-Exos could reduce reactive oxygen species production in human umbilical vein endothelial cells by regulating SIRT3/SOD2 under high glucose conditions, thereby increasing the level of oxidative stress and promoting diabetic wound healing.

AD-MSCs’ exosomes also induced cell proliferation and differentiation with angiogenesis. Huang et al¹¹⁶ showed that AD-MSCs’ exosomes silencing NFIC were able to promote the proliferation and migration of human venous endothelial cells with vascular proliferation under high glucose conditions by regulating the miR-204-3p/HIPK2 signaling axis. Parvanian et al¹¹⁷ Waveform proteins were loaded into AD-MSCs exosomes, which were engineered to promote the proliferation and migration of fibroblasts as demonstrated by in vivo and in vitro experiments. Zhou et al¹¹⁸ injected model mice with AD-MSCs exosomes, which were found to promote wound healing, accelerate re-epithelialization, reduce the width of the scar, as well as promote vascular regeneration. In addition, Hsu et al¹¹⁹ found that AD-MSCs’ exosomes stimulated resident monocytes/macrophages to secrete more TGF-β1 and activated the TGF-β/Smad3 signaling pathway, which promoted more proliferation and activation of fibroblasts, and played a role in diabetic wound recovery.

AD-MSCs’ exosomes demonstrated significant anti-inflammatory, immunomodulatory, and oxidative stress modulation, as well as cell proliferation and angiogenesis promotion abilities in DFU treatment. In addition, AD-MSCs’ exosomes can be obtained by autologous harvesting, which is easier to obtain than exosomes from other stem cell sources. This autologous harvest not only reduces the risk of immune rejection but also lowers the cost of treatment. These features make it more promising for clinical application in DFU trauma.

BM-MSCs Exosomes

BM-MSCs exosomes are derived from bone marrow and are rich in a variety of stem cell growth factors and immunomodulatory factors, which have strong angiogenic and anti-inflammatory effects, as well as strong effects in immunomodulation, and are suitable for DFU wounds accompanied by chronic inflammation and immune abnormalities.

Exosomes from BM-MSCs accelerate the proliferation of diabetic wound cells and thus aid in wound healing. Pomatto et al¹²⁰ compared exosomes from bone marrow-derived MSCs with exosomes from bone marrow-derived MSCs and found that both ADSC- and BMSC-derived exosomes exerted beneficial effects on cells involved in cutaneous wound healing (eg, fibroblasts, keratinocytes, and endothelial cells). Hou et al¹²¹ reported that BM-MSCs’ exosomes could enhance the migration and proliferation of human umbilical vein endothelial cells by activating the AKT signaling pathway. Chen et al¹²² showed that BM-MSCs’ exosomes can regulate cell viability, proliferation, migration, and vascularization through the PI3K/Akt signaling pathway. In addition, Saccu et al¹²³ found that BM-MSCs’ exosomes accelerate wound healing by regulating cell death, inflammatory response, and angiogenesis in injured tissues. In addition, Lu et al¹²⁴ showed that high levels of BM-MSCs’ exosomal MiRNA-29a could be taken up by human umbilical vein endothelial cells and promote their proliferation, migration, and tube formation. BM-MSCs’ exosomes also inhibited diabetic wound inflammatory response. Geng et al¹²⁵ prepared a carboxyethyl chitosan-dialdehyde carboxymethylcellulose hydrogel loaded with bone marrow-derived MSC-Exo for the treatment of diabetic wounds and was found to be effective in modulating the inflammatory microenvironment of wounds and promoting the conversion of M1-type macrophages to M2-type, in addition to promoting neovascularization. In addition, BM-MSCs’ exosomes have been shown to affect dendritic cells, transforming them into immature and immunosuppressive regulatory dendritic cells. They can inhibit the activation and proliferation of autoreactive T cells by releasing IL-10, and play an immunomodulatory role.¹²⁶

According to previous studies, BM-MSCs’ exosomes are able to enhance cell proliferation and migration and promote wound healing by activating signaling pathways such as AKT and PI3K/Akt. In addition, it can regulate the inflammatory microenvironment, promote the conversion of M1-type macrophages to M2-type, inhibit the inflammatory response, and play an immunomodulatory role. These properties give it great potential for application in DFU treatment.

Exosomes of UC-MSCs

UC-MSCs exosomes are derived from umbilical cords, which have strong immunomodulatory and regenerative abilities, and their lower immunogenicity avoids triggering a strong immune response during treatment, which is advantageous in the aspect of DFU wound treatment.

UC-MSCs’ exosomes can regulate inflammation and thus promote diabetic wound healing. Yan et al⁶⁴ found that UC-MSCs exosomes could accelerate diabetic wound healing in an in vitro assay by modulating oxidative stress injury in endothelial cells. Xiang et al¹²⁷ injected UC-MSCs exosomes into diabetic rats by the tail vein and found that they could significantly reduce the production of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in the blood of rats. UC-MSCs’ exosomes were injected into the tail vein of diabetic rats and were found to significantly reduce the production of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in the blood of rats. In addition, exosomes of UC-MSCs can promote cell proliferation, migration, and neovascularization, and enhance the regenerative ability of tissue cells. Liang et al¹²⁸ found that exosomes released from UC-MSCs treated with high glucose, and the circHIPK3 within the exosomes can significantly inhibit apoptosis, and promote cell proliferation, migration, and regeneration of blood vessels. Zhu et al¹²⁹ experiments showed that UC-MSCs exosomes promoted the growth and migration of dermal fibroblasts, and also significantly promoted cutaneous nerve repair, and played an important role in wound healing. These studies indicate that UC-MSCs’ exosomes can effectively regulate inflammation, reduce the level of pro-inflammatory cytokines, promote cell proliferation, migration, and neovascularization, enhance tissue regeneration, and promote skin nerve repair (see Table 2). It significantly promotes diabetic wound healing and shows good therapeutic potential.

Stem Cell Exosome Composite Bioscaffold Material for the Treatment of Diabetic Foot Wounds

Exosomes released by stem cells contain a variety of bioactive substances inside, such as proteins and RNA, which can play an important role in DFU wound repair. However, the half-life of exosomes in wounds is too short, which seriously hampers their repair efficacy. For this reason, researchers have turned their attention to composite bioscaffold materials. The slow release of exosomes through the scaffold material allows it to act on the wound continuously and stably and forms a support structure at the wound to provide physical support for the exosomes. In DFU wound treatment, combining MSC-Exos with the scaffold material complex can play a synergistic role in accelerating DFU wound healing.

Hydrogel Scaffolds

The composition and structure of hydrogels are similar to the natural extracellular matrix and are biocompatible. In addition, hydrogels have slow-release properties, as they release exosomes slowly, allowing for a sustained and stable effect on the wound. Because of these properties, many scientists have developed composite scaffolds based on hydrogels.

Shi et al¹³⁰ developed and prepared a multifunctional hydrogel based on gallic acid-conjugated chitosan and partially oxidized hyaluronic acid, with which they piggybacked MSC-Exos of hypoxic bone marrow origin. The composite scaffolds constructed by them were found to improve the stability of the exosomes, enable stable and sustained release of the exosomes, and increase the efficiency of the exosomes’ uptake by target cells. Han et al¹³¹ developed A composite hydrogel of filipin and filaggrin proteins to harbor human umbilical cord-derived MSC-Exos, which showed good wound healing promotion effects. Peng et al¹³² developed a multifunctional hydrogel scaffold combining chitosan-grafted dihydrocaffeic acid, benzaldehyde-capped Pluronic^®F127, tannins, and adipose-derived MSC-Exos. Derived MSC-Exos to form a hydrogel network, this composite hydrogel scaffold significantly accelerated diabetic wound healing. In addition, Wu et al¹³³ constructed a composite excipient of chitosan hydrogel and adipose-derived MSC-Exos and demonstrated that exosomes could be slowly released from the dressing with the degradation of chitosan hydrogel and accelerated skin wound healing. These findings suggest that the hydrogel scaffold improves exosome stability, enhances target cell uptake efficiency, and significantly accelerates diabetic wound healing. Hydrogel encapsulation enhances exosome stabilization and retention at the wound site through physical and chemical methods. Physical methods include adsorption of exosomes into the hydrogel through non-covalent interactions, while chemical methods stabilize the binding of exosomes to the hydrogel matrix through covalent cross-linking or self-assembling peptide cross-linking. In addition, the tissue adhesion and shape adaptation properties of hydrogels can further improve exosome retention at the wound site and promote wound healing. Moreover, its low immunogenicity and easy preparation make it show a broad application prospect in DFU treatment, and it is expected to become an effective new treatment.

3D Bioprinted Scaffolds

3D bioprinting is an advanced biotechnology that combines biomaterials, biomolecules, and living cells to print biomedical structures that create three-dimensional structures of tissues and organs by depositing biomaterials layer by layer.^134–136 The use of 3D bioprinting technology enables personalization and precise construction of scaffolds according to the shape, depth, and size of DFU trauma, which is conducive to precise treatment.¹³⁷ 3D bioprinting technology offers higher precision and complex structure building capabilities compared to traditional scaffold manufacturing techniques, enabling personalization while operating under cell-friendly conditions to improve cell activity and biocompatibility. In addition, its rapid prototyping and high throughput characteristics give it an advantage in mass production.¹³⁸ With the deepening of related research, 3D bio-printed scaffolds are expected to become an effective solution for DFU trauma treatment.

Ferroni et al¹³⁹ developed a bioscaffold for carrying the release of MSC-Exos by 3D printing using methacrylate hyaluronic acid bio-ink. The biocomposite scaffold was experimentally found to sustain the release of MSC-Exos and to promote DFU wound healing. Hu et al¹⁴⁰ Utilized extrusion-based 3D printing technology and combined decellularized small intestinal submucosa, mesoporous bioactive glass, and exosomes to create a 3D scaffold dressing. It was found that this composite scaffold dressing could sustain the release of biologically active exosomes and that the scaffold could accelerate wound healing by promoting angiogenesis in diabetic wounds. In addition, Wu et al¹⁴¹ constructed a hydrogel scaffold containing adipose-derived MSC-Exos and nitric oxide using 3D bioprinting, and this composite scaffold could effectively promote the migration and angiogenesis of human umbilical vein endothelial cells.

The above studies indicate that 3D bioprinting technology combined with stem cell-derived exosome scaffolds can effectively carry and release exosomes to promote DFU wound healing and angiogenesis, which has a large clinical application prospect. Such composite scaffolds provide an innovative model for DFU treatment.

Discussion and Conclusion

MSC-Exos are nanovesicles with diverse biological functions that exhibit important roles in the treatment of DFU. They accelerate the repair process of diabetic wounds through various mechanisms such as modulating the local inflammatory response of wounds, enhancing neoangiogenesis, and promoting cell proliferation. However, despite the promising efficacy of MSC-Exos in laboratory studies, its translation into clinical care still faces many challenges, mainly in terms of regulatory barriers and the need for standardized isolation protocols. On the regulatory side, the lack of uniform standards for the production of MSC-Exos, the imperfect safety assessment, and the fact that global regulators have yet to develop specific guidelines increase the difficulty of clinical application. On the technical side, existing isolation methods are inefficient and poorly scalable, making it difficult to meet clinical needs. Therefore, the development of efficient, reproducible, and scalable separation techniques and the establishment of a standardized production process are key to achieving clinical translation of MSC-Exos. In addition, the delivery route, stability, and targeting of exosomes need to be studied in depth to ensure their safety and efficacy in clinical applications. Currently, clinical trials of exosomes are still in the preliminary stage, and more clinical data are needed to support their therapeutic efficacy and safety in the future.

To further enhance the therapeutic efficacy of MSC-Exos in DFU, many innovative technologies have emerged, such as hydrogel scaffolds and 3D printing technology. Hydrogel scaffolds can provide a favorable microenvironment for the release of exosomes, thus enhancing the therapeutic effect, while 3D printing technology can be used to precisely control the delivery and distribution of exosomes, further enhancing their effectiveness in DFU treatment. The integration of these technologies is expected to provide more possibilities for personalized treatment in the future.

Although MSC-Exos shows promising prospects in DFU therapy, there are still many challenges in its technological translation and clinical application. First, the preparation process and quality control of exosomes should be strengthened to ensure their efficiency and consistency in the production process. Second, a safer and more effective delivery system should be explored to improve the targeting and stability of exosomes. Finally, interdisciplinary cooperation should be strengthened, such as the combination of biomaterials, nanotechnology, and clinical medicine, which will pave the way for the clinical application of MSC-Exos.

In summary, MSC-Exos shows a large clinical application prospect in the treatment of DFU. With continuous technological advances and intensive research, MSC-Exos have been shown to have great therapeutic potential, promising to change the existing treatment landscape 490-49.

Acknowledgments

The authors gratefully acknowledge the support from the Shenzhen Platform of Trauma Rescue and Regenerative Medicine, the Bao’an District Clinical Medical Research Center for Trauma, and the High-quality Development Research Project of Shenzhen Bao’an Public Hospital. We also thank all team members for their dedication and contributions to this work, and look forward to continued collaboration in future research.

Funding

This project was supported by the Sanming Project of medicine in Shenzhen (No. SZSM202106019 and 202208).

Disclosure

The authors report no conflict of interest in this work.

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