As physicians, we are constantly dealing with sports injuries. While they are typically not seen as life-threatening with high chances of recovery, they could potentially cause further problems down the line for the patient. Sports injuries can also take months to heal and getting patients back on their feet can take a lot of time, effort and money, which can be frustrating for patients who want to get back to playing football every weekend or for those who have a skiing holiday booked in the next month.
Recently, there has been a massive surge in the use of stem cells as an alternative treatment to common sports injuries. This article aims to outline the benefits and risks attached to using stem cells and how this alternative treatment may help patients who are suffering from common sports injuries.
What Are The Most Common Sports Injuries?
We are constantly treating sports injuries on a regular basis. Some of the most common sports injuries doctors typically deal with are:
An ankle sprain occurs when the ligaments in the ankle are stretched and eventually torn due to twisting or falling onto the foot. Ankle sprains are common among athletes and sports enthusiasts, however, if left untreated, the ankle can weaken, making it more vulnerable to further damage. This leads to long term problems such as chronic ankle pain, arthritis, and ongoing instability.
A sprained ankle can be easily diagnosed when we see displays of swelling, bruising, stiffness and pain when we attempt to touch or move the ankle.
A groin pull is basically a groin strain. Strains occur when the muscles are overstretched, moving in directions that are not normal for them or pulled too forcefully or suddenly. This leaves them torn and damaged and results in tenderness and bruising in the groin and inner thigh area. This injury is common in athletes that play sports which require a lot of quick side-to-side movements.
A groin pull can be easily diagnosed after a thorough physical examination of the symptoms and possible tests such as x-rays and MRI’s.
A hamstring strain occurs when the three muscles in the back of the thigh are overstretched from movements such as hurdling and kicking the leg out sharply. As these muscles are naturally tight and susceptible to sprains, it can take from six to twelve months to heal and are vulnerable to recurring injuries. Poor or lack of stretching are the likely causes of a pulled hamstring.
Shin Splints is an inflammation of the muscles in the lower leg when they are overworked and stressed. Shin splints are often found in athletes that engage in sports that require a lot of running, dodging or quick stops and starts.
Knee injury: ACL tear
An ACL knee injury is a tear or sprain of the ligament that holds the leg bone to the knee. Sudden stops or changes in direction can tear the ACL and make that dreaded “pop” sound. Almost immediately, the knee will swell, feel unstable and be too painful to bear weight. This injury is common in athletes that engage in sports such as soccer, basketball, and downhill skiing.
ACL tears are commonly seen as a severe sports injury and can be traditionally treated with rehabilitation programs and surgery to strengthen or completely replace the torn ligament.
Knee injury: Patellofemoral Syndrome
Patellofemoral Syndrome occurs when repetitive movements of the kneecap (patella) are made against the thigh bone (femur) which damages the tissue. This knee pain is common among young adults and can be caused by a number of factors such as weakness in the thigh or buttock muscles, tight hamstrings, short ligaments around the kneecap or alignment problems through the feet.
Tennis Elbow (epicondylitis)
Tennis Elbow is common for athletes that play sports such as tennis or golf that require the player to ‘grip’ tightly and repetitively for an extended amount of time. This results in the ligaments of the forearm becoming strained and inflamed, making it painful to make wrist or hand motions.
What Are The Traditional Treatment Options & Management Strategies For Sports Injuries?
Traditional treatment methods and strategies for treating mild sports injuries such as sprains and strains can be done at home. Traditional advice given by doctors can include taking rest, applying ice to reduce the swelling and dressing the injury with compression bandages to support and assist healing. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may also be prescribed to help reduce swelling and to relieve pain.
Moderate severity injuries may be traditionally treated with immobilization strategies such as the use of crutches or a cast brace to assist the ankle to heal for the first few weeks. This may be followed with rehabilitation exercises to strengthen the ankle and prevent stiffness and future problems.
Severe sports injuries such as knee injuries are traditionally treated with surgery or rehabilitation programs to replace or restore the torn ligaments or muscles. This also goes for those patients who experience persistent problems after months of nonsurgical treatment.
Whatever the severity level of the sports injury, the healing process can take up to several months before the muscle restores to its natural condition. Injuries can also leave muscles and ligaments permanently weakened and susceptible to further injury.
Is Stem Cell Therapy An Option For Treating Sports Injuries?
The use of stem cells to treat sports injuries are becoming more popular due to its ability to grow new blood vessels that facilitate faster and better healing, decrease or prevent inflammation and release proteins (cytokines) that can slow down tissue degeneration and reduce pain. Sports injuries that include damage to tendons, ligaments, muscles, and cartilage are reported to be seeing the best results from stem cell therapy.
Dr. Bill Johnson, MD of Innovations Medical sees stem cell therapy as a revolutionary alternative to painful surgery and long recovery and states that,
“Patients who undergo stem cell therapy for their sports injury report a reduction in their painful symptoms and increase range of motion and increased mobility. Stem cell therapy helps to quickly reduce joint inflammation, and many patients see improvements in 1 to 2 days. Anti-inflammatory results of the procedure can last for 2 to 3 months and many patients see a gradual improvement in their condition over time.”
Even celebrity athletes such as Peyton Manning and Ryan Tannehill have used stem cell treatment in conjunction with traditional treatments with success. Stem cells are placed directly into the joint via surgical application or injection to aid quicker healing and promote the growth of cells needed to restore strength and flexibility in muscles and ligaments.
However, using stem cells as an alternative method to treat sports injuries is still a controversial subject and is very much still debated among medical professionals. Research is still undergoing to show whether or not stem cell therapy is the best solution. Critics of this therapy argue the fact that stem cell therapy doesn’t work any better than a placebo and that there is no clear evidence that this type of therapy is safe. Unwanted side effects can include swelling and pain and if stem cells are used from other sources or manipulated in any way, this can result in a higher risk of developing tumors.
Although a rare neurologic condition, Amyotrophic Lateral Sclerosis (ALS) is the most common type of Motor Neuron Disease (MND), a condition that affects the voluntary muscles. This is a progressive disorder that leads to muscle weakness and depletion due to nerve dysfunction.
ALS is also called Lou Gehrig’s disease, named after the football player who had this condition. The literal meaning of Amyotrophic is ‘no muscle nourishment’ which becomes the cause of muscle atrophy. ‘Lateral’ refers to the group of nerves in the spinal cord that sends signals to the muscles. It is these nerves that degenerate, leading to sclerosis in this region. In later stages, this affects the nerves that control breathing and hence can be fatal.
The initial symptoms of ALS include stiffness and muscle weakness, which gradually involves all the muscles under voluntary control. The affected regions and progressive pattern vary from one person to another. Some having difficulty holding a pen or a cup while others finding difficulty speaking, chewing or even talking. Thus, ALS is an ailment that affects daily life and makes simple tasks painful and troublesome.
According to the Center for Disease Control and Prevention (CDC), 14,500 to 15,000 people had ALS in the United States in 2016, with approximately 5000 people having a confirmed diagnosis for the condition annually. Although the average survival rate is three to five years, patients can live for ten years or more.
Are there different types of ALS?
Amyotrophic Lateral Sclerosis has two types:
Sporadic ALS: this is the most common one and affects 95% of sufferers. This type occurs without a clear cause.
Familial ALS (FALS): This type occurs in 5-10% of sufferers. This type of ALS is genetic and runs in families. This occurs due to abnormal changes to a gene that is then passed in generations.
What are the symptoms of ALS?
Early signs and symptoms might be unnoticeable and become perceptible after some time. Most clinical signs are evident of upper motor neuron and lower motor neuron lesion. The limb onset ALS (70%) involves initial symptoms in the limbs while the bulbar onset ALS (25%) is characterized by speech and swallowing problems. This is followed by weakness in the limbs later. The remaining 5% of the patients have respiratory involvement in the early period. 
Most common symptoms include:
- Muscle weakness in the limbs (distal or proximal)
- Asymmetric progressive muscle wasting
- Difficulty in motor activities like walking, talking, chewing
- Weakness in arms, legs, hands, and feet
- Muscle cramps and twitching
- Slurred speech
- Emotional liability (episodes of uncontrolled laughing and crying)
- Difficulty in maintaining posture and gait
- Difficulty in breathing and swallowing
With the progression of the disease, symptoms may spread to all parts of the body. In some patients, frontotemporal dementia may occur resulting in poor memory and decision-making abilities.
What Causes ALS?
The exact cause of ALS has not been known by scientists to date. However, research is being carried out to understand what causes ALS. There are several different factors such as:
Studies have shown that 5 to 10% of cases of ALS are caused by genetic mutations. For example, changes to the gene that makes SOD1 protein causes damage to motor neurons.
No major association has been established between environmental factors like toxins, viruses, diet or physical trauma and the risk of development of ALS. However, there is ongoing research on the subject. Studies have shown that some athletes are at a higher risk of acquiring ALS due to vigorous physical activity.
Glutamate is the neurotransmitter that is in control of signals to and from the brain. Accumulation of this neurotransmitter within the spaces surrounding the nerves damages them.
Research has also shown mitochondrial structural and functional abnormalities, as well as defects in axonal structure and transport, could be the causative agents for ALS.
How Do We Diagnosis ALS?
When it comes to diagnosis, there are no specific tests that can provide a definitive diagnosis for ALS. However, doctors conduct a series of tests to rule other similar diseases. A full medical history check and a neurologic examination are undertaken at regular intervals to assess the progressive worsening of symptoms.
Running the following Image testing diagnostic tests can help reach a diagnosis:
- Electromyography (EMG) – EMG records the electrical activity of the muscle fibers.
- Nerve Conduction Study (NCS) – NCS assesses the electrical activity of the nerves and muscles.
- Magnetic Resonance Imaging (MRI) – MRI rules out other possible conditions such as a tumor or cyst in the spinal cord, cervical spondylosis, or a hernia in the neck that could be causing the nerve compression.
Laboratory tests such as blood screening and urine tests can also be carried out so that other diseases can be eliminated.
What Are The Treatment Options & Management Strategies For ALS?
ALS is managed through a multidisciplinary approach.
Unfortunately, there is no definitive cure for the disease at this time. Management of ALS is done through symptomatic treatment to ease the condition of the patients and prevent unnecessary complications:
Support – Physicians, psychologists, speech therapists, nutritionists, and home care assistance all play a vital role in making life easier for patients with ALS.
Medication – Riluzole (Rilutek) and Edaravone (Radicava) are the drugs approved by the U.S Food and Drug Administration (FDA) for treating ALS. Riluzole is believed to reduce glutamate levels thereby, decreasing damage to the motor neurons. Edaravone acts an antioxidant and is believed to expel free radicals and reduce the oxidative stress in the motor neurons.
Lifestyle Habits – Physiotherapists can recommend exercise and physical activity like walking, swimming, and bicycling that may improve muscle strength and help elevate mood without overstressing the muscles.
Speech Therapy – therapists can help patients with ALS to employ strategies to speak clearly. They may also recommend computerized aids such as speech synthesizers and eye-tracking technology to help people learn ways for responding by nonverbal means.
Diet – Nutritionists may formulate a diet plan for patients, which consists of food that is easy to swallow and provides enough nourishment and calories for the patients to maintain adequate energy levels and to prevent excessive weight loss
Breathing Support – Patients with ALS may suffer from shortness of breath and difficulty breathing during physical activity or while lying down. If this is the case, doctors can recommend Non-Invasive Ventilation (NIV) that provides breathing support through the nose or mouth. NIV improves quality of life and increases the number of years of survival for patients.
Is Stem Cell Therapy An Option?
As previously mentioned, there is no curable treatment for ALS available. However, scientists are researching Stem Cell Therapy as the new favorable approach in the treatment of neurologic disorders.
There is a rising interest in Stem Cell Therapy as a promising remedy for curing ALS. Mesenchymal stem cells are particularly believed to be the most suitable ones due to their availability, absence of ethical issues and positive results in various experiments.
Studies and clinical trials have begun to apprehend the benefits of MSC transplantation. They demonstrate that MSCs lead to a partial recovery of motor neurons and a delay in disease progression. Also, there has been no evidence of a major adverse effect after MSC transplantation.
When testing this newfound research on animals, the lifespan of the subjected animal has increased with MSC transplantation. These positive results have encouraged the administration of MSC in ALS patients.
However, despite the safe outcomes of MSC transplantation in humans, results show that there is only a partial improvement in ALS sufferers with only a few cases that showed a delay in disease progression. Hence, there is a need for further studies and trials on a higher number of human subjects for a better understanding of MSC effects so that more significant conclusions can be reached.
The Keto Diet: A Miracle Formula Or A Dangerous Risk?
We live in a world overloaded with diets and eating plans that are all preaching miracle, long term results for weight loss and reducing risks of developing illnesses and diseases.
But, with so many different plans out there all claiming to produce the best results, it’s hard to know which one to recommend to your patients. The Paleo, the Atkins, the Pritikin Principle, the South Beach, WeightWatchers, The Zone Diet… the list goes on and on. Recently, many doctors are leaning more towards THE KETO DIET as a recommendation for not only their overweight patients; but patients that suffer from various illnesses and ailments.
WHAT IS A KETO DIET?
To put it simply, a ‘keto’ or ‘ketogenic’ diet is a low-carb, high-fat diet.
A reduction in carbohydrates puts the body into a metabolic state called ketosis. This is when the body produces small fuel molecules called ketones. Carbs are broken down into glucose and used for energy. So when someone deprives themselves of carbs, the body has no choice but to switch its fuel supply from glucose (blood sugar) to ketones found in body fat.
Therefore, as long as carbs are restricted, the body is constantly burning fat.
Kathleen M. Zelman, MPH, RD, LD told WebMD that a ketogenic diet is often used for losing weight, but it can help manage certain medical conditions such as epilepsy, heart disease, diabetes type 2, brain diseases and IBS.
WHAT ARE THE MAIN BENEFITS OF A KETO DIET?
Weight Loss & Appetite Suppression
The biggest benefit of the keto diet and the one most dieters are striving for is weight loss and suppression of appetite.
Typically, the body takes their fuel from our stores of glycogen, but with the reduction of carbohydrates in a keto diet, glucose levels are lowered and the body is forced to obtain its energy from body fat. This results in patients experiencing weight loss.
Food cravings and hunger is often the reason that our patients are failing at dieting. Another key reason why medical professionals have found the keto diet to be so successful is because of the effects it has on reducing cravings and tackling hunger.
Studies have proven that participants that follow a low-carb diet have reported a decrease in appetite and cravings compared to individuals following a low-fat diet. This is possibly down to high-fat foods slowing down the process of gastric emptying. Food that is high in fat passes through the gut at a much slower pace, leaviing the individual feeling satisfied for longer.
Diabetes Type 2
Diabetes Type 2 is triggered by spikes occurring in the patient’s blood sugar levels. Insulin is used to regulate and control these spikes. When a patient with type 2 diabetes follows a keto diet, the amount of glucose they are consuming dramatically decreases due to the lower intake of carbohydrates.
So the lower intake of glucose found in high carb food = the lower intake of insulin.
A study of 21 overweight men with type 2 diabetes who were put on a keto diet showed that most participants saw a reduction in their insulin medication or were taken off diabetes medication completely as a result of controlling their glucose levels by following a keto diet.
A keto diet has been used to treat epilepsy since the 1920s and during a recent study, seventy percent of epileptic patients have reported less and more controlled seizures and a reduction in their medication since implementing a keto diet.
Epileptic seizures occur when a network of neurons fire unexpectedly due to the overexcitement of brain cells releasing neurotransmitters, like glutamate. The brain is then not able to suppress the spread of excitability like in non-epileptic people using inhibitory neurotransmitters like gamma-aminobutyric acid, or GABA.
What a keto diet can do to control seizures is to reduce the amount of glutamate in the brain and enhance the synthesis of GABA.
Alzheimer’s Disease & Dementia
A ketogenic diet can contribute towards keeping the brain young and healthy and reduce the risk of developing degenerative brain diseases such as Alzheimer’s disease and dementia.
Findings from a study found that keto diets can protect neurovascular function against cognitive decline by clearing out beta-amyloid protein in the brain. Beta-amyloid creates toxic plaques that interfere with neuronal signaling that results in Alzheimer’s disease and dementia. Improvements to blood flow to the brain, which contributes to healthy cognitive function, were also noted.
IBS & Other Gastronomical Conditions
Fifteen percent of the general population claim to suffer from IBS. It is one of the most common complaints taken to doctors. A lot of research has been undertaken in recent years around the effect that carbohydrates have on the gastrointestinal system.
Studies have found that when sufferers consume carbohydrates, they tend to ferment in the small intestine and causes gas and bloating. For IBS sufferers, carbs are poorly absorbed by the gut wall, causing fluid to remain in the intestinal space, resulting in diarrhea.
Therefore, when IBS sufferers follow a keto diet and reduce their intake of carbohydrates, they report significant improvements to their condition.
All these amazing results from consuming low-carb, high-fat foods sounds promising, right?
Medical professions at Harvard Medical School are urging medical professionals to be wary of recommending the keto diet to their patients. They have identified numerous risks associated with following a ketogenic diet.
Not only is the body being deprived of an essential food group – carbohydrates, but a keto diet is typically high in saturated fat. High levels of saturated fat can lead to high cholesterol and heart disease.
Other risks they have been identified with following a keto diet is:
A deficiency in micronutrients including selenium, magnesium, and vitamins B and C which are found in most of the fruit and vegetables that are restricted in a keto diet.
Liver problems due to the amount of fat the body needs to metabolize. This can cause existing liver problems to worsen.
Kidney problems due to the amount of protein the body needs to metabolize. A keto diet can put strain on the kidneys and make exisitng conditions worse.
Constipation. The keto diet is low in fibrous foods like grains and legumes. The digestive system relies on a steady flow of fiber to break down foods and get rid of body waste.
“The Keto Flu” is a term for the mood swings, body aches and brain fuzz that people experience when following a keto diet. The brain needs glucose to function and when it is deprived of this, it can cause irritability and tiredness.
We want to know your thoughts and opinions on the Keto Diet!
Have you ever recommended the keto diet to your patients? Do you see the benefits happening in your patients? Is it dangerous?
JAMES P. ALLISON, PhD
Chair, department of immunology, and director.
Immunotherapy Platform, MD Anderson Cancer Center
Losing his mother to lymphoma and two uncles to melanoma and lung cancer taught James P. Alli- son, PhD, a difficult lesson at an early age. “My mother was treated with radiation and my uncle, who had lung cancer, was treated with chemotherapy. I saw the ravages of those treatments, which ultimately were unsuccessful,” he says.
Allison knew he wanted to work in cancer research, developing more effective and less toxic therapies. An undergraduate course at the University of Texas at Austin sparked his interest in T cells—warrior cells of the immune system that defend the body against infections and cancer.
In October, Allison won the 2018 Nobel Prize in Physiology or Medicine jointly with Japanese Tasuku Honjo, MD, PhD. Alison has spent more than 30 years studying how T cells work and what turns the immune system on and off against cancer. The 1980s discovered the T Cell antigen receptor, which he described as the cell’s “ignition switch.” A few years later, he showed that a molecule called CD28 acts as the “gas pedal.” Finally, he found that CTLA-4, a protein on the surface of T cells, is the “brake,” signaling the immune system to stop the millions of T cells from attacking the cancer.
The next step, he says, was to pre vent the brakes from engaging—“to give the T cells time to keep going and eliminate the tumors.” Allison’s work led to the development of drugs called checkpoint blockade antibodies, including ipilimumab (Yervoy) for melanoma. “When we started this work, the median life expectancy with metastatic melanoma was 11 months, and no drug had ever changed that,” he says. Among people treated with Yervoy, more than 20% are still alive three years later, and some have survived 10 years.
New drugs targeting another off-switch, PD-1, have since been developed to treat cancers of the head and neck, lung, kidney, and bladder, among others. Now Allison’s lab is studying different combinations of checkpoint blockades to see which patients will respond best to them. “I don’t think these approaches are going to replace any. of the traditional therapies,” he says, but, “I think that soon, immunotherapy is going to be part of every successful cancer therapy.”
However, despite the alarming rate of death from opioid overdose, this problem is not grabbing the headlines from the media for health stakeholders to pay more attention and look for ways to finding lasting solutions to the anomaly.
It is worthy to note that, while many people are addicted to opioids in the form of heroin and synthetic opioids, millions of people are out there, taking an overdose of opioids in the form of pain reliever prescription for chronic pains and other related health issues. Though, opioids are used in the treatment of chronic pain, research has suggested that they may not help relieve pain in the long-term. This has posed a serious threat to public health and economic welfare, not only for the United States but other affected countries as well.
According to the Centers for Disease Control and Prevention, the total “economic burden” of only opioid misuse prescription in the US is estimated as $78.5 billion per year, inclusive of lost productivity, criminal justice involvement, healthcare cost, and addiction treatment.
This article aims to look at how we come to this point, some facts about opioids in the United States, and some useful information about opioid overdose. Read on to uncover them all.
Opioids and Substance Abuse at a Glance.
Opiates, popularly known as narcotics, are commonly prescribed for quick pain relief and sleep inducement. Originally, it is derived from poppy plant seeds or their byproducts. Opiates occur naturally in the form of opium and morphine, but most opiates are synthetic. These drugs became highly addictive because they create an intense sense of euphoria and as well as safeness, when adding it to pain-relieving properties.
Most patients with pain disorders later turn to rely on pharmaceutical opiates like oxycodone and hydrocodone; hence, they become addicted to it. However, opioid overdose has been studied to cause a number of health problems in the users, and these health issues are not limited to serious disorders, but even death. One of the prolonged effects of opioid usages is the brain’s inability to produce endorphins naturally. Endorphins are known to be the body’s natural painkillers.
Initially, around late 1990s, when opioids were becoming popular among the people, pharmaceutical companies came out to allay the fear of the people and reassure the medical community that opiate users would not become addicted to opioids prescribed for pain relief; hence, healthcare service providers started prescribing the drugs to patients at greater rates. Subsequently, this act resulted in a extensive misuse and diversion of these drugs prior to the time it was discovered that opioid prescriptions could actually be highly addictive like other opiates.
Facts about Opioid Prescription and Misuse in America.
The rates of opioid overdose in the United States started increasing in 2017 with over 47,000 citizens died due to misuse of opioids, such as heroin, prescription opioids, illicitly manufactured fentanyl (one of the powerful opioid synthetics). In the same year, this number was estimated 1.7 million and 652,000 Americans suffered from prescription opioid pain relievers and heroin use disorder respectively. The question is, how does it start?
It all starts when the body cannot properly manage and regulate pain again. In this condition, an opiate user may become addicted to the drugs, as the drugs now used to relief their pain and at the same time, create a sense of contentment and happiness in using them. Over time, even after the pains have gone, an opiate user will require more of the substance to reach the same level of high that creates happiness and contentment which they first experienced; hence, the person is already “an opiate addict.” Withdrawing from its use makes it even worse, as their bodies begin to show some unpleasant symptoms that make the user seeking more to relieve the symptoms.
From here, opioid prescription and misuse have turned out to become a public health problem in the United States with alarming rates of death on a daily basis.
Below are some facts about the opioid crisis in the United States:
- According to WQAD Digital Team’s claim of IMS Health’s market research, the number of opioid prescriptions doctors dispensed increased from 112 million to 282 million from 1992 to 2012 respectively. However, according to IQVIA, the number has declined to 236 million in 2016 and further dropped by 10.2% in 2017.
- Centers for Disease Control and Prevention, about 68% of cases of estimated 70,200 drug overdose deaths recorded in 2017 were linked to the use of opioids. This is more than six times compared to that of 1999 (including illegal opioids such as heroin and illicitly manufactured fentanyl and prescription opioids).
- According to a review, about 21 – 29% of patients with chronic pain who take opioids prescription misuse them.
- Another study also claimed that roughly 80% of heroin users initially misused prescription opioids.
- The same study also claimed that about 8 – 12% of opiate users develop an opioid use disorder.
- According to the Centers for Disease Control and Prevention, there is a 30% increase in opioid overdoses in 45 states of the United States between July 2016 to September 2017.
- In another review, opioid overdoses were seen increasing by 70% in the Midwestern region between July 2016 to September 2017.
What is been doing about it?
With over two million opioid dependants in the United States, the U.S. Department of Health and Human Services (HHS) is making efforts to tackle the opioid crisis in America by focusing on five major areas. These include:
- Promoting and enlighten people on the use of overdose-reversing drugs.
- Giving people access to treatment and recovery therapies.
- Offering support for modern research on addiction and pain.
- Promoting public health surveillance to help people understand the epidemic better.
- Enhancing better pain management practices in the country.
In furtherance to the efforts of the U.S. Department of Health and Human Services (HHS), the National Institutes of Health (NIH)’s Director Francis S. Collins in April 2018’s National Rx Drug Abuse and Heroin Summit, announced the launch of a special program referred to HEAL (Helping to End Addiction Long-term) Initiative. HEAL is an aggressive effort set up to expedite scientific solutions to address the opioid crisis in the United States.
Just because media are not paying attention to the opioid crisis in the US does not mean things are working in the medical world. With the alarming rate of opioid overdose and an increasing number of Americans abusing prescription and becoming dependent on opioids, all hands must be on deck to find a lasting solution to the current problem. While different agencies and stakeholders are not relenting on their efforts, more medical developments and approaches are still required to achieve a good result.
Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: an update at 3 year follow-up
The management of chondral disease is challenging because of its intrinsic poor healing potential. Biomechanical and biological changes may lead to the loss of tissue homoeostasis, resulting in an accelerated degeneration of the articular surface, eventually leading to end-stage osteoarthritis (OA).
Conservative therapies for the treatment of knee degenerative processes, such as non-pharmacological interventions, systemic drug treatment and intra-articular therapies are used before resorting to surgery; nonetheless, they may offer only short-term benefits. Encouraging preliminary results have been reported using mesenchymal stem cells (MSCs), either alone or in association with surgery. Among the many sources of MSCs, adipose tissue has created a huge interest in the context of cartilage regeneration (Pak et al. 2016; Ruetze and Richter 2014), due to its wide availability, ease to harvest and richness in mesenchymal cell elements within the so called stromal vascular fraction (De Girolamo et al. 2016; Caplan 2008; Caplan and Correa 2011; Caplan and Dennis 2006). Moreover, MSCs from adipose tissue are characterized by marked anti-inflammatory and regenerative properties, which make them an excellent tool for regenerative medicine purposes (De Girolamo et al. 2016; Caplan 2008; Caplan and Correa 2011; Caplan and Dennis 2006). Nevertheless, preparation of autologous MSCs for injection requires ex vivo culture from a good manufacturing practice facility, which makes the process laborious and expensive (Ährlund-Richter et al. 2009; Arcidiacono et al. 2012; Sensebé et al. 2010). An increasing number of adipose tissue-derived cell isolation systems, allowing for minimal manipulation, have been developed in the last years. We previously reported the safety and feasibility of autologous micro-fragmented adipose tissue as adjuvant for the surgical treatment of diffuse degenerative chondral lesions at 1 year follow-up (Russo et al. 2017). Here we present the outcomes of the same cohort of patients evaluated at 3 year follow-up.
The original study was approved by the Ethics Committee of Verona and Rovigo – Italy (protocol n° 10,227, March 1st, 2016). An extension of the study protocol has been conceded by the same authority to evaluate the results at 3 years (protocol n° 14,505, March 14th 2018) and written informed consent was obtained from all patients.
Study design and population, surgical techniques, post-op rehabilitation protocol, safety and clinical evaluation were previously described (Russo et al. 2017). Briefly, 30 patients, affected by diffuse degenerative chondral lesions of different degrees of severity, were treated with autologous and micro-fragmented adipose tissue between 1stJanuary 2014 and 31st December 2014. Of these 30 patients, 24 (80%) also had an associated surgery (ACL/LCL reconstruction, high tibial osteotomy, meniscectomy), while six (20%) underwent arthroscopy alone. For the 3 year follow-up all the patients were re-contacted and clinically evaluated by the same clinicians.
Of the 30 patients treated with autologous micro-fragmented adipose tissue, eight also had meniscal surgery, five plate removal, three osteotomy, two ligament surgery, two microfractures, and four other surgical procedures. The remaining six had arthroscopy alone. Despite the heterogeneity of the associated surgical procedures all the patients shared the presence of chondral lesions of different degrees of severity (Russo et al. 2017).
Table 1: Background data of the failures (n = 7)
FC femoral condyle, TP tibial plateau, PF patellofemoral.
No adverse events, lipodystrophy cases at the harvesting site nor atypical inflammatory reactions at the joint level were reported in the 3 year period for all the 29 patients.
|Grade chondropathy (ICRS classification)|
FC femoral condyle, TP tibial plateau, PF patellofemoral.
The main finding of this study is that the beneficial effect of autologous micro-fragmented adipose tissue as adjuvant for the treatment of diffuse degenerative chondral lesions is maintained in the mid-term. In addition, no complications were observed in the 3 year period showing the safety profile of this procedure. No patient, including the seven patients who received additional treatments, worsened compared to the pre-operative condition.
Despite the heterogeneity of the associated surgical procedures all the patients shared the presence of chondral lesions of different degrees of severity, which may have been responsible for the impairment in function and pain.
As reported in literature, articular surface damages, especially when diffused (three compartment OA), positively correlate with a decay in the outcomes in patients who received knee surgery for other reasons (Bonasia et al. 2014; Røtterud et al. 2012; Saithna et al. 2014; Su et al. 2018; Verdonk et al. 2016). Published data shows a decline in the clinical results in the mid to long-term for arthroscopic and chondral debridement procedures in cases of initial knee OA (Su et al. 2018). Some authors assessed the effectiveness of the arthroscopic or conservative treatments in patients diagnosed with knee OA (Kellgren-Lawrence grade 2 to 4) with 5 years of follow-up, concluding that arthroscopy provided no benefit in decreasing or delaying arthroplasty and that it can relieve symptoms only up to 2 years (Su et al. 2018). The same observation has been reported for ligament reconstruction, where the short and mid to long-term benefits are inferior in patients who have cartilage lesions. In a study of a cohort of ACL-injured patients with full-thickness cartilage lesions (ICRS grade III–IV), the authors showed that ACL-injured patients with full-thickness cartilage lesions reported worse outcomes and minor improvement after ACL reconstruction compared to patients without cartilage lesions at 2–5 years follow-up, although no significant differences between the two groups at the time of ACL reconstruction were present. This means that the observed differences between the groups must have occurred during the follow-up period (Røtterud et al. 2012). Furthermore, the outcomes of osteotomy procedures in patients with diffuse degenerative knee chondropathy worsen in the mid to long-term (Bonasia et al. 2014; Saithna et al. 2014). In a study reporting the results of a case series of opening wedge distal femoral varus osteotomies for valgus lateral knee OA, it is shown that re-operation for non-arthroplasty related surgery was common due, besides others, to infection and persistence of symptoms (Saithna et al. 2014). With regard to meniscectomy, in a recently published paper it is concluded that meniscus therapy including partial meniscectomy, meniscus suture, and meniscus replacement has proven beneficial effects in long-term studies in patients without cartilage damage, supporting the hypothesis that meniscectomy increases the risk of cartilage degeneration (Verdonk et al. 2016).
Based on the aforementioned published evidences, we should have expected, in the mid-term, a decay of the outcomes. Notably, the results have been maintained with no significant differences in all the evaluated parameters with respect to the 1 year follow-up assessment. Furthermore, in line with that already observed at 1 year, the patients with lesions in more than one compartment had higher and statistically significant improvements compared to patients with lesions in only one compartment (p < 0.01). This finding supports our hypothesis of using micro-fragmented adipose tissue for the treatment of the diffuse degenerative knee pathology as an adjuvant of the surgical procedures. Indeed, the maintenance of stable results at the last follow-up leads to hypothesize a protective role of micro-fragmented adipose tissue in a further chondral degeneration.
The seven patients who received additional biological therapies in the 3-year period, were young (mean age 36.3 ± 7.3 vs. 44.7 ± 11.4), very active in sport and 6 out of 7 had a patellofemoral chondropathy. Their conditions after 1 year did not worsen, but they probably needed an additional biological treatment because of their high functional demands and the presence of the patellofemoral chondropathy, which is a negative prognostic element, even if the small number of patients does not allow for any statistical correlation.
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Autologous mesenchymal stem cell application for cartilage defect in recurrent patellar dislocation: A case report
Recurrent patellar dislocation is a repeated dislocation that follows from an initial episode of minor trauma dislocation . Conservative management gives a minimal result in re-dislocation, with persistent symptoms of anterior knee pain, instability and activity limitation. Meanwhile, there is no gold standard treatment of realignment procedures. This can further cause cartilage lesion in the patella and femoral condyle, and consequently increase the risk of re-dislocation. Mesenchymal stem cells (MSCs) have been widely explored for treating cartilage defect due to their potency of chondrogenic differentiation. We present a novel approach of treating cartilage lesions in recurrent patellar dislocation by combining of arthroscopic microfracture and autologous bone marrow derived MSCs (BM-MSCs) after Fulkerson osteotomy.
Presentation of case.
A 21-year-old male presented with left knee discomfort. Ten years ago, the patient felt discomfort on the medial side of the knee and felt his knee cap slide out laterally. The patient experienced several episodes of instability ranging from a feeling of “giving away” until a prominent lateral sliding-off of his knee cap. Anterior knee pain has also occurred during activities such as climbing stairs or exercising.
Physical examination revealed slight pain on the anterior side of the patella, but no atrophy or squinting patella. Knee range of motion (ROM) was normal when the knee cap position was normal, but was limited when it was dislocated (0–20°). Lateral subluxation of the patella was found when the knee was extended from 90° flexion position (J-sign positive), positive patellar apprehension test, with medial patella elasticity/patellar glide >2 quadrants. The Q angle, in the 90° flexed knee position, was 10°, which was still normal. The plain radiograph imaging showed no abnormality. Insall-Salvati index was 1.12. The patient was diagnosed with recurrent patellar dislocation, with suspected cartilage lesion of the left knee.
The first surgery was an arthroscopy diagnostic and distal realignment procedure (lateral retinaculum release, percutaneous medial retinaculum plication, and antero-medialization of tibia tubercle/Fulkerson osteotomy). We found articular cartilagedefects on the lateral condyle of the femur with a diameter of 3 cm (Figure. 1A), and on the postero-medial with a diameter of 2.5 cm (Figure. 1B), and the depth of both was more than 50% of the cartilage thickness. We determined that the articular defect was Grade 3 according to International Cartilage Regeneration & Joint Preservation Society (ICRS). We performed a dissection of lateral retinaculum (lateral release) (Figure. 1C) using an electrocautery, continued by incising the medial side of tibia tuberosity and detaching the patellar tendon by using an oblique osteotomy procedure on tibia tuberosity, where the fragment slide 1 cm antero-medially and fixed with two 3.5 mm (length 40 mm) partial threaded cancellous screw, followed by percutaneous plication on the medial side of the patella using non-absorbable string (Figure. 2A). Post-operative ROM was 90° flexion without any dislocation (Figure. 2B) and the position of the screws was good (Figure. 2C).
Figure 1.A. Cartilage defect on the femoral lateral condyle with a diameter of 3 cm (pointed by the arrow). B. Articular cartilage defect on posteromedial patella with a diameter of 2.5 cm (pointed by the arrow). C. Lateral retinaculum dissection/lateral release using an electrocautery (pointed by the arrow).
Figure 2.A. Percutaenous medial plication using non-absorbable string no.2. B. Post-operative anteroposterior and lateral projection of plain radiograph imaging. C. Post-operative CT scan.
One month after surgery, full ROM and weight bearing exercises were started, including knee exercise until maximum flexion was reached along with quadriceps muscle exercise. Eighteen month after that surgery, we performed an iliac crestbone marrow aspiration; arthroscopic microfracture by using an awl until 4 mm depth was reached on the site located ±3–4 mm from the articular cartilage defect on the posteromedial patella and femoral lateral condyle (Fig. 3A); and tibial tuberosity screw removal.
Outcomes were assessed by using International Knee Documentation Committee (IKDC) score, visual analog scale (VAS) score and imaging. Baseline IKDC score was 52.9 and VAS score was 8. Nineteen months after the first surgery, IKDC score was improved to 93.1, while the VAS score decreased to 2. Six months after MSCs implantation, evaluation by MRI FSE cor T2-weighted signal (cartilage sequence) showed a significant growth of articular cartilage covering most of the defect (Figure. 4). Two years after the MSCs implantation, there was no complaint and full ROM was reached.
Recurrent patellar dislocation are uncommon problem, with recurrence rate 15%–44% after conservative management, while cartilage lesions following recurrent patellar dislocations are quite common, but still no gold standard or consensus on the management. This patient was diagnosed as chondromalacia Grade 3 Outerbridge classification and Grade 3 ICRS. One of the suitable procedures for recurrent patellar dislocation with chondromalacia, especially Grade 3 or 4, was Oblique Fulkerson-type osteotomy, with or without the release of lateral retinaculum. This distal realignment procedure could decrease patellofemoral pain by anteriorization of tibial tuberosity, decreasing articular contact pressure and at the same time medializing knee extensor mechanism. Therefore, we performed the Fulkerson-type osteotomy with lateral retinacular release, combined with percutaneous medial plication since the patient was already 21 years of age and the bone was expected to be mature so that the risk of premature physeal closure in proximal tibia can be avoided. This technique has demonstrated good results (86%), although it had a risk of tibial stress fracture in the healing process. The lateral retinacular release is an adjuvant after tibial tubercle medialization to re-center the patella. It was reported that isolated lateral retinacular release significantly gives an inferior long-term result compared to medial reefing. Percutaneous plication of medial patella procedure was indicated to build a strong construct by shortening the patellofemoral ligament, in order to prevent lateral sliding of the patella.
Treatment of articular cartilage defect remains challenging since it has limited self-healing capacity. Lesions that do not reach the subchondral zone will be unlikely to heal and usually progress to a cartilage degeneration. Limited blood supply in the cartilage and low chondrocyte metabolic activity disrupt natural healing that is supposed to fill the defect by increasing hyaline cartilage synthesis activity or stem cell mobilization from bone marrow to site of injury. The proper initial procedure for chondral lesion >4 cm2 was marrow stimulation by mosaicplasty or microfracture; and for a lesion <4 cm2 and >12 cm2 accompanied with symptoms, autologous cartilage implantation (ACI) beneath a sutured periosteal flap was promising. This procedure could not regenerate cartilage in the long term, due to loss of flap or cell suspensions. A scaffold (e.g. HA) was then used to act as an anchorage for chondrocytes adherence on cartilage defects and to promote the secretion of chondrocyte extracellular matrix. The BM-MSCs implantation could be an alternative source of the chondrocytes. Human BM-MSCs are relatively easy to isolate and to be cultured in such a condition that may retain their capability to differentiate into chondrocytes.
The MSCs effect was reported as effective as ACI and even had the advantage over ACI in terms of the number cells obtained, better proliferation capacity and less damage in the donor site. Treating large cartilage defects by using BM-MSCs showed good outcome, but the transplantation procedure was invasive. Wong et al. conducted a clinical study of the BM-MSCs intra-articular injection in combination with high tibial osteotomy (HTO) and microfracture for treating cartilage defect with varus knee. They reported that intra-articular MSCs injection improved the outcomes in the patients undergoing HTO and microfracture. Here we performed also a less invasive approach by injecting the autologous BM-MSCs intra-articularly, following the arthroscopic microfracture using an awl to penetrate the subchondral bone plate in the cartilage defects, which led to clot formation. This clot contains progenitor cells, cytokines, growth factors and pluripotent, marrow-derived mesenchymal stem cells, which produce a fibrocartilage repair with varying amounts of type-II collagen content. Cytokine within the fibrin clot will attract the injectable stem cells to the cartilage lesions.
The HA injection in this patient was aimed to suspend the MSCs and to support regenerative potency of MSCs with chondroinductive and chondroprotective potency of HA. Intraarticular injection of MSCs suspended in HA could be an alternative treatment for large cartilage defect. Supporting microfracture technique by intra-articular HA injections had a positive effect on the repair tissue formation within the chondral defect. The MRI showed that there was a growth of articular cartilage covering most of the defect even though it was not perfect as yet.
This case report demonstrated that combining Fulkerson osteotomy with the lateral retinacular release and percutaneous medial plication was effective in treating chronic patellar instability. The combination of microfracture and MSCs implantation was safe and could regenerate the articular cartilage in this patient.
1Gynecology and Oncology Department of the Second Hospital of Jilin University, Ziqiang Street 218, Changchun 130000, China
2Medical Research Center, Second Clinical College, Jilin University, Ziqiang Street 218, Changchun 130000, China
Received 11 August 2017; Revised 5 November 2017; Accepted 22 November 2017; Published 19 December 2017
Academic Editor: Changwon Park
Mesenchymal stem cells have been at the forefront of regenerative medicine for many years. Exosomes, which are nanovesicles involved in intercellular communication and the transportation of genetic material transportation that can be released by mesenchymal stem cells, have been recently reported to play a role in cell-free therapy of many diseases, including myocardial infarction, drug addiction, and status epilepticus. They are also thought to help ameliorate inflammation-induced preterm brain injury, liver injury, and various types of cancer. This review highlights recent advances in the exploration of mesenchymal stem cell-derived exosomes in therapeutic applications. The natural contents, drug delivery potency, modification methods, and drug loading methods of exosomes are also discussed.
Mesenchymal stem cells (MSCs) originate from the mesoderm of many tissues, including bone marrow, liver, spleen, peripheral blood, adipose, placenta, and umbilical cord blood, and have the capacity to self-renew and the ability to generate differentiated cells. Over the last decade, MSCs have emerged as a popular research topic because of their potential role in regenerative medicine, immunoregulation, neuroprotection, and antitumor effects originally attributed to direct cell replacement. However, experimental data indicates that most MSCs are largely cleared, while a small proportion will integrate into injured tissue after intravenous injection . Furthermore, the “cell replacement theory” does not account for the sufficient durations in a variety of disease models [2, 3]. Recently, several mechanisms have been put forward regarding the therapeutic potential of MSCs, including (1) paracrine factors involving proteins/peptides and hormones and (2) the transfer of mitochondria or exosomes/microvesicles packaging multitudinous molecules .
Exosomes are a family of nanoparticles with a diameter in the range of 40–100 nm that are generated inside multivesicular endosomes or multivesicular bodies (MVBs) and are secreted when these compartments fuse with plasma membrane . Exosomes are enriched in endosome-derived components as well as many bioactive molecules such as proteins, lipids, mRNAs, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), transfer RNA (tRNA), genomic DNA, cDNA, and mitochondrial DNA (mtDNA) [6–12]. It has also been reported that exosomes may be released from multiple cell types, including reticulocytes , immunocytes, tumor cells, and MSCs . This suggests that the secretion of exosomes is a general cellular function that plays an important role in the intercellular transfer of information.
In this review, we focus on the mechanisms of exosomes/microvesicles, covering the current knowledge on biological characteristics and their potential cell-free therapeutic applications for MSC-derived exosomes.
2. Characterization and Isolation of Exosomes
Exosomes were first discovered by Harding’s group as “a garbage can” in maturing sheep reticulocytes . Originally, they were thought to have a typical “cup-shaped” or “saucer-like” morphology when analyzed by electron morphology [15, 16]. Zabeo’s group revealed a wide diversity in exosome morphology when purified from homogeneous cell types (the human mast cell line HMC-1). They classified exosome morphology into nine categories: (1) single vesicle; (2) double vesicle; (3) triple vesicle or more; (4) small double vesicle; (5) oval vesicle; (6) small tubule; (7) large tubule; (8) incomplete vesicle; and (9) pleomorphic vesicle . This categorization suggested that different morphologies of exosomes may be accompanied by various and specific functions. Exosomes also contain surface proteins unique to the endosomal pathway, which are generally used to characterize exosomes and distinguish them from microvesicles (MVs), apoptotic bodies, and other vesicles (Table 1), such as tetraspanins (CD63, CD81, and CD9), heat shock proteins (Hsc70), lysosomal proteins (Lamp2b), the tumor-sensitive gene 101 (Tsg101), and fusion proteins (CD9, flotillin, and annexin) [12, 18]. Exosomes are released in almost all types of extracellular fluids, including blood, urine, amniotic fluid, ascites, hydrothorax, saliva, breast milk, seminal fluid, and cerebrospinal fluid. Exosomal content greatly depends on cellular origin. For example, exosomes derived from B lymphocytes that bring functional MHCI, MHCII, and T cell costimulatory molecules can stimulate T cell proliferation . Furthermore, cancer cell-derived exosomes contain gelatinolytic enzymes and other cell adhesion-related molecules to help tumor progression and metastasis . Importantly, these cancer cell-derived exosomes are actively incorporated by MSCs in vitro and in vivo, in that the transfer of exosomal proteins and miRNAs acquire the physical and functional characteristics of tumor-supporting fibroblasts [21, 22]. For more details on the molecular cargos and extracellular signal transmission pathway of exosomes, the reader may refer to ExoCarta (http://www.exocarta.org) or EVpedia (http://evpedia.info), as well as the American Society for Exosomes and Microvesicles (http://www.asemv.org), for an in-depth exploration.
Ultracentrifugation and a commercial kit rooted in polymer-based precipitation are the most well-established purification protocols . Other conventional validated isolation methods described in the literature include ultrafiltration, chromatography, and affinity capture . New protocols have been established in order to facilitate the large-scale and high-purity manufacture of exosomes. Microfluidic techniques  are based on electrochemical, electromechanical, viscoelastic , optical, nonoptical, and other principles, yet the isolation is a mixed population of small nanoparticles without further demonstration of their intracellular origin. Thus, we use the term exosomes in this review to refer to extracellular vesicles characterized by exosome-specific surface markers, regardless of the primitive appellations in the published data.
3. Cargos and Functions of MSC-Derived Exosomes
The abundance of cargos identified from MSC-derived exosomes attracts broad attention because of their therapeutic potential in cardiovascular disease, tissue (kidney, liver, skin, and cornea) repair, immune disease, tumor inhibition, and neurological disease (Figure 1). They function largely via the constant transfer of miRNAs and proteins, resulting in the alteration of a variety of activities in target cells via different pathways.
Over 900 species of proteins have been collected from MSC-derived exosomes according to ExoCarta. With the exception of some common proteins involved in cell metabolism and the cytoskeleton, many proteins have been found in different tissue sources of MSC-derived exosomes. Proteomic studies by Kang’s group identified 103 proteins from neural stem cell-derived exosomes. For example, the presence of polymyositis/scleroderma autoantigen 2 (PM/Scl2), a highly specific nuclear autoantigen, indicates that exosomes may be involved in triggering autoimmunity. They also found an imparity between exosomes larger than the baseline (50 nm) and those of smaller morphology . These findings may explain the phenomenon recently observed by Caponnetto et al. regarding size-dependent cellular uptake of exosomes by target cells . Intriguingly, all enzymes involved in the ATP synthesis of glycolysis (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), phosphoglucomutase (PGM), enolase (ENO), and pyruvate kinase m2 isoform (PKm2)), as well as the rate-limiting glycolytic enzyme phosphorylated PFKFB3 that upregulates phosphofructose kinase, were identified in MSC-derived exosomes. Furthermore, oxidative stress was reduced via peroxiredoxins and glutathione S-transferases in MSC-derived exosomes , which suggests that replenishing glycolytic enzymes to increase ATP production, as well as additional proteins to reduce oxidative stress through exosomal transportation, may help reduce cell death in myocardial ischemia/reperfusion injury. Comparable levels of VEGF, extracellular matrix metalloproteinase inducer (EMMPRIN), and MMP-9 have also been reported in MSC-derived exosomes.
These three proteins play a vital role in stimulating angiogenesis , which could be fundamental for tissue repair. Recent experimental evidence summarized by Burrello suggests that transcriptional factors, such as Nanog, octamer-binding transcription factor 4 (Oct-4), HoxB4, and Rex-1, play an important role in the immune system . For example, HoxB4 has been shown to affect DC maturation and T-cell proliferation, differentiation, and activation through WNT signaling. Interestingly, membrane proteins and exosome-specific surface markers, such as CD81, CD63, and CD9, may affect the immune response by regulating cell adhesion, motility, activation, and signal transduction . Several studies have also shown that exosomes derived from MSCs harbor cytokines and growth factors, such as TGFβ1, interleukin-6 (IL-6), IL-10, and hepatocyte growth factor (HGF), which have been proven to contribute to immunoregulation .
miRNAs consist of a class of small noncoding RNAs that regulate gene expression posttranscriptionally by targeting mRNAs to induce suppression of protein expression or cleavage . Many miRNAs have been found in MSC-derived exosomes and are reportedly involved in both physiological and pathological processes such as organism development, epigenetic regulation, immunoregulation, tumorigenesis, and tumor progression. Notably, exosomes with membrane structure act as preservers and deliverers of miRNAs, transferring functional miRNAs into recipient cells. It has been reported that exosomal miR-23b, miR-451, miR-223, miR-24, miR-125b, miR-31, miR-214, and miR-122 [33, 34] may inhibit tumor growth and stimulate apoptosis through different pathways. For instance, miR-23b promotes dormancy in metastatic breast cancer cells via the suppression of the target gene MARCKS, which encodes a protein that promotes cell cycling and motility . MiR-16, shuttled by MSC-derived exosomes, has also been found to suppress angiogenesis by downregulating VEGF expression in breast cancer cells .
Recently, let-7f, miR-145, miR-199a, and miR-221, which are released from umbilical MSC-derived exosomes, have been found to largely contribute to the suppression of hepatitis C virus (HCV) RNA replication . Di Trapani’s group evaluated the immunomodulatory effects exerted by MSC-derived exosomes on unfractionated peripheral blood mononuclear cells and purified T, B, and NK cells. They observed that exosomes had higher levels of miRNAs compared to MSCs and could also induce inflammatory priming via increasing levels of miR-155 and miR-146, which are two miRNAs involved in the activation and inhibition of inflammatory reactions . Similar immunosuppressive functions have also been reported in animal experiments by Cui et al. . Exosomes from MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features by regulating inflammatory responses and restoring synaptic dysfunction . Recent studies have also shown that aging is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs . However, contradictions regarding these outcomes remain. A quantitative analysis of exosomal miRNA abundance and stoichiometry by Chevillet’s group quantified both the number of exosomes and the number of miRNA molecules in replicate samples isolated from diverse sources. Regardless of the source, the study indicated that, on average, over 100 exosomes would need to be examined to observe one copy of a given abundant miRNA, suggesting that most individual exosomes do not carry biologically significant numbers of miRNAs and are thus unlikely to be functional individually as vehicles for miRNA-based communication .
In 2006, MSC-derived exosomes that could modulate the phenotype of target cells, supporting self-renewal of hematopoietic progenitors and multipotency by transfer of growth factors and mRNA, were first reported. For instance, exosomal SOX2 was found to initiate innate responses against microbial infection through neutrophil activation . Although MSC-derived exosomes have the same morphology as exosomes from other cells and carry typical markers, they are quite different in regard to compartmentalization and protein and RNA composition. For example, studies have indicated that not all MSC-derived exosomes are equivalent . Baglio’s group  characterized the small RNAome of exosomes released by early passage adipose-MSCs (ASC) and bone marrow-MSCs (BMSCs). They found a large discrepancy in the proportion of miRNAs in total small RNA content between cells (19–49%) and exosomes (2–5%), suggesting that the miRNAs in exosomes do not merely reflect the cellular content. Further studies regarding the overrepresentation of small RNA content-tRNAs revealed a similar outcome. The most abundant tRNA in ASC exosomes, tRNA GCC (Gly), represented only a small fraction (5%) of the total cellular tRNA. Importantly, the authors also determined that the striking differences in tRNA species seemed to be associated with the differentiation status of MSCs. Recent research has shown that the stability of exosome composition is susceptible to localized environmental conditions. For example, hypoxia and inflammatory signals, such as lipopolysaccharides, may be strong interference factors .
4. Exosomes as Drug Delivery Vehicles
Optimal features of drug delivery vehicles may be applied to improve carrier qualities, including cellular tropism, efficient therapeutic cargos, appropriate physicochemical properties, and sufficient immune tolerance. Among the many drug platforms, liposomes have been the preferred pharmaceutical vehicles for drug delivery. A wide range of liposome products have been approved for the treatment of diseases, including fungal infections, pain management, hepatitis A, influenza, and various types of cancer [44, 45]. In contrast to liposomes, exosomes are optimal for drug delivery because of their natural properties and plasticity with minor modifications. Here, we compare exosomes and liposomes and suggest that exosomes may be a promising star for drug delivery.
4.1. Exosomes versus Liposomes
Exosomes and liposomes are both coated with a phospholipid membrane. The membrane structure of exosomes is inlayed with multiple natural biomolecules, such as surface proteins and MHCs, while liposomes may be modified with targeting ligands or inert polymeric molecules such as oligosaccharides, glycoproteins, polysaccharides, and synthetic polymers . The size of liposomes is in the range of 30 nm to several microns . Smaller liposomes (as small as exosomes) display a prolonged circulation time compared to larger ones, but the capacity for optimal drug reservation and release profiles is partly lost. For more details regarding circulation time and biodistribution, readers can refer to other sources . Regarding cellular interactions and uptake, liposomes can be equipped with targeting ligands, which can bind to receptors or other molecules that are specific or overexpressed by target cells for interactions and the intracellular delivery of drugs . However, the drug delivery of liposomes is not efficient, since many modifications have been designed to minimize clearance and poisonousness. In general, liposomes accumulate in the macrophages of the liver and spleen after intravenous injection. Few liposomes are interspersed in other tissues, which may be due to the lack of immunocompatibility. On the other hand, exosomes are born with many features of an ideal drug delivery vehicle. For example, they exhibit lower toxicity compared to liposomes. In addition, they are well tolerated by the immune system, even across the blood-brain barrier, avoiding phagocytosis or degradation by macrophages . Exosomes exhibit an innate targeting tendency. For instance, MSC-derived exosomes home preferentially to inflamed tissues and tumor tissues . Furthermore, abundant bioactive materials within exosomes or on the surface provide primitive treatment potential, and there are abundant modification methods for membrane targeting and drug loading. Alvarez-Erviti et al. engineered dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide and loaded these modified exosomes with siRNAs by electroporation. These intravenously injected exosomes showed a strong knockdown of BACE1 (mRNA (60%) and protein (62%)), a therapeutic target of Alzheimer’s disease, in wild-type mice .
4.2. Exosomal Modification and Cargo Loading
To amplify the therapeutic effects, many studies try to modify and load various treatment factors into exosomes via various methods. To date, these methods can be classified into two categories: (1) loading after isolation and (2) loading exosomes during biogenesis.
The first approach has been applied to load chemotherapeutic agents, siRNAs, and miRNAs. To reduce immunogenicity and toxicity of doxorubicin, Tian’s group facilitated exosomal tumor targeting by engineering mouse immature dendritic cells (imDCs) to express a well-characterized exosomal membrane protein (Lamp2b) fused to a breast cancer-specific iRGD peptide (CRGDKGPDC). Chemotherapeutic agents were loaded via electroporation. The results showed an encapsulation efficiency of up to 20% and exosomal-delivered doxorubicin specific to breast cancer cells in vitro, leading to strong antiproliferative activity without overt toxicity after intravenous injection of BALB/c nude mice . For nucleic acid, electroporation method has also been the first-rank used reported in several studies [49, 51]. Although these studies provided positive delivery outcomes, debates remain. Some studies indicate that siRNA encapsulation is an illusion caused by nonspecific aggregate formation, independent of the exosomes. In addition, no significant encapsulation of siRNA could be measured when aggregate formation was blocked . Therefore, it is necessary to establish multiple protocols for loading exosomes with nucleic acid.
The second approach is based on transfection methods to package active proteins, nucleic acid, and other active molecules into exosomes, where cells are transfected with an engineered effector-expressing vector. Liu’s group used this method to load cells with opioid receptor Mu (MOR) siRNA in order to treat drug addiction via downregulating the expression of MOR, the primary target for opioid analgesics used clinically, including morphine, fentanyl, and methadone. This novel study provided a new strategy for the treatment of drug addiction . Similarly, synthesized RNA oligonucleotides were transferred to MSCs in order to produce miR-143-rich exosomes, inhibiting the migratory potential of osteosarcoma cells . Akt was transfected into umbilical cord-derived MSCs by using an adenovirus transfection system that improved cardiac function in animals treated with modified exosomes . In addition, Pascucci reported that MSCs can acquire strong antitumor properties after incubation with paclitaxel (PTX), including the uptake of high drug doses followed by release into exosomes, inhibiting tumor growth activity. This method provides the possibility of using MSCs for the development of drugs with a higher cell-target specificity . Sterzenbach reported the usage of the evolutionarily conserved late-domain (L-domain) pathway as a mechanism for loading exogenous proteins into exosomes . They labeled an intracellular target protein with a WW tag, which was recognized by the L-domain motifs on Ndfip1, resulting in the loading of the target protein into exosomes.
For better tissue-targeting and an enhanced exosomal therapeutic effect, surface modification of exosomes was recently attempted by many groups using gene transfection techniques. The conventional method for surface protein loading was the expression of a genetic fusion between the targeted peptide and a protein that natively localized on the exosomal surface, such as Lamp2 . Similarly, Ohno and colleagues engineered donor cells to express the transmembrane domain of platelet-derived growth factor receptor fused to the GE11 peptide, which efficiently delivered let-7a miRNA to epidermal growth factor receptor- (EGFR-) expressing breast cancer cells . Furthermore, Tamura modified the exosomal surface by a simple mixing of original exosomes and cationized pullulan through an electrostatic interaction of both substances, thus targeting injured liver tissue and enhancing the therapeutic effects .
The fate of nucleic acid cargos in target cells remains controversial. For example, Kanada et al. suggests that exosomes cannot deliver functional nucleic acids to target cells by detecting differential fates of transfection-loaded biomolecules (plasmid DNA (pDNA), mRNA, and siRNA) delivered to target cells .
4.3. MSCs as an Ideal Source of Exosomes for Drug Delivery
Despite the fact that the properties of natural MSC-derived exosomes are disputed and distinctive of different origins, the use of MSC-derived exosomes has been confirmed for the cell type-specific targeting of drug delivery as a better alternative because of several features. First, exosomes do not elicit acute immune rejection, and there is no risk for tumor formation . Second, MSCs are efficient mass producers of exosomes, which can be manufactured large scale in culture , providing support for individualized therapy. Third, the safety of exosomes has been confirmed in vivo by different animal models [63, 64]. To achieve cell-specific targeted drug delivery, several studies have tested donor cells, loading methods, and therapeutic cargos of MSC-derived exosomes. Bone marrow stem cells are typically used as the donor cells, and miRNAs are typically used for therapeutic cargos (Table 2). A phase II-III study has also been processed by a group in Egypt, who hypothesized that intravenous infusion of cell-free umbilical cord blood-derived MSC microvesicles may reduce the inflammatory state, thus improving the β-cell mass and glycemic control in patients with type 1 diabetes (T1DM). However, these outcomes remain controversial, particularly in reference to dose responses. The data reported in several studies is highly dependent on the drug-loading of exosomes, not the quantity of exosomes.
5. Exosomes for Cell-Free Therapy
Currently, the use of exosomes as early diagnostic tools for various types of cancer is underway. In addition, the use of exosomes as diagnostics for prostate cancer is undergoing FDA-approved tests. While complexities surrounding the therapeutic potential of exosomes continue to unravel, several clinical trials (Table 3, data from http://clinicaltrials.gov) have been completed or are underway in order to evaluate this therapeutic potential. In these trials, largely modified exosomes were used rather than native exosomes.
6. Conclusion and Perspective
The therapeutic potential of exosomes presents exciting new avenues for intervention in many diseases. The ability instinct to transport genetic messages and to protect the cargos to natural preferential recipient cells has drawn a rapid rise in attention. Therefore, specialized journals and websites have been established to disseminate this continuously unraveling information. While various clinical trials are underway to evaluate the safety and effectiveness of exosomes as therapeutic targets, many issues still remain. Questions regarding how clinical-grade exosomes can be produced in quantity and how various loading and isolation strategies impact the potency of exosome-based drug delivery remain unanswered. Therefore, there is an urgent need to closely examine the following aspects of exosomes: (1) natural therapeutic potential; (2) biogenesis mechanism; and (3) circulation kinetics and biodistribution. There is still a long road ahead, from promising phenomenological observations to clinical applications.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this article.
This study was supported by grants from the National Natural Science Foundation of China (81302242), Jilin Province Science and Technology Funds (20150204007YY and 20140204022YY), and Jilin Province Development and Reform Commission funds (2014G073 and 2016C046-2).
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UCLA researchers have discovered a new way to activate the stem cells in the hair follicle to make hair grow. The research may lead to new drugs that could promote hair growth for people with baldness or alopecia, which is hair loss associated with such factors as hormonal imbalance, stress, aging or chemotherapy. Hair follicle stem cells are long-lived cells in the hair follicle that are present in the skin and produce hair throughout a person’s lifetime. They are quiescent, meaning they are normally inactive, but they quickly activate during a new hair cycle, which is when new hair growth occurs. The quiescence of hair follicle stem cells is regulated by many factors. In certain cases, they fail to activate, which is what causes hair loss.
The study by Heather Christofk, PhD, and William Lowry, PhD, both of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, found that hair follicle stem cell metabolism is different from other cells of the skin. Cellular metabolism involves the breakdown of the nutrients needed for cells to divide, make energy and respond to their environment. The process of metabolism uses enzymes that alter these nutrients to produce metabolites. As hair follicle stem cells consume the nutrient glucose — a form of sugar — from the bloodstream, they process the glucose to eventually produce a metabolite called pyruvate. The cells then can send pyruvate to their mitochondria — the part of the cell that creates energy — or convert pyruvate into another metabolite called lactate.
The research team first blocked the production of lactate genetically in mice and showed that this prevented hair follicle stem cell activation. Conversely, in collaboration with the Rutter lab at the University of Utah, they increased lactate production genetically in the mice, which accelerated hair follicle stem cell activation, increasing the hair cycle.
The team identified two drugs that, when applied to the skin of mice, influenced hair follicle stem cells in distinct ways to promote lactate production. The first drug, called RCGD423, activates a cellular signaling pathway called JAK-Stat, which transmits information from outside the cell to the nucleus of the cell. The research showed that JAK-Stat activation leads to the increased production of lactate, and this in turn drives hair follicle stem cell activation and quicker hair growth. The other drug, called UK5099, blocks pyruvate from entering the mitochondria, which forces the production of lactate in the hair follicle stem cells and accelerates hair growth in mice.
“Lactate Dehydrogenase Activity Drives Hair Follicle Stem Cell Activation,” Nature Cell Biology, August 14, 2017
ISSCA has launched a new stem cell training web page designed to offer free information and resources to help physicians choose a training program best suited to their unique needs.
MIAMI, June 26, 2018—The International Society for Stem Cell Application (ISSCA) has launched a new stem cell training course web page, coordinated by Global Stem Cells Group affiliate Stem Cell Training, designed to help physicians access free information and resources on the newest instruction and training options in regenerative medicine training.
The new web page is designed to help physicians interested in adding stem cell procedures to grow their medical practice or enhance career advancement opportunities find stem cell training program options to enable them to find a training program best suited to their individual needs. ISSCA’s variety of stem cell training opportunities include:
• Online stem cell training course, ISSCA’s cutting-edge online course that teaches physicians everything they need to know to add adult stem cell-based procedures to their existing practice, or confidently transition to a regenerative medicine center. Offering the convenience of training from a home or office computer, this course prepares physicians in all the theoretical and practical knowledge needed to effectively and expertly administer stem cell therapies to patients, including harvesting and isolating stem cells.
ISSCA’s online training positions physicians to open their own stem cell center practice and join ISSCA’s expansive network. Successful completion of the online training course allows physicians to immediately begin offering cutting-edge regenerative medicine procedures to patients, establish themselves as experts in their fields, and enjoy the benefits of the growing regenerative medicine industry.
• Hands-on stem cell certification training courses, ISCCA’s intensive, two-day hands-on training course scheduled at various international locations provides attending physicians with expert instruction on autologous stem cell therapies in the field of regenerative medicine. Participants learn techniques and protocols for harvesting and isolating stem and regenerative cells from adipose tissue, bone marrow, and /or peripheral blood from live patients and administering the cells back to the patient
Course curriculum consists of comprehensive theoretical lectures and home study education, and two days of didactic and clinical experience. One day of post-educational on-site clinical assistance is also available upon request.
• Onsite training, ISSCA’s personalized, hands-on, onsite stem cell training brings stem cell specialists to your practice or clinic, anywhere in the world, to provide one-on-one training tailored to your practice’s specific requirements—saving time and money. The onsite training program offers participants a unique opportunity to grow their practice and achieve their specific practice goals by offering practice-specific regenerative medicine treatments to patients in their medical office or clinical setting.
The onsite training course provides participating practices with personalized theoretical information and hands-on training along with ongoing support for their clinical practice. Applications and protocols are provided by a Stem Cells Training faculty member with extensive experience in laboratory and clinical practice.
ISSCA’s onsite training specifications include:
1. Equipment and supply delivery. The Stem Cell Training team
delivers and sets up all equipment and supplies necessary for the training session to take place and will leave the physician’s team
fully qualified to start its own stem cell treatment practice.
2. Expert trainers. ISSCA’s onsite stem cell training course takes a highly visual and interactive approach. Expert trainers teach and supervise the hands-on process using live patients and different protocols for the extraction, isolation, and application of PRP, adipose- and bone marrow-derived stem cells.
3. Multimedia access. ISSCA provides physicians participating in its onsite training program access to its library of high-resolution, step-by-step procedure videos and ongoing online and telephone support for clinical equipment, inquiries or concerns for the practice’s future use and reference.
• Fellowship in cell therapy and tissue engineering. Recognizing the need for knowledge of stem cell protocols among physicians and healthcare professionals, ISSCA and Stem Cell Training created the Fellowship of Stem Cell Therapy and Tissue Engineering program. The fellowship focuses on stem cell therapies involving the potential replacement of cells or organs that are diseased, injured, infirmed, ailing or aged
In this modular training program, a group of experienced academic scholars involved in stem cell transplantation present a series of topics covering the general principles and practices of stem cell
biology and evidence-based treatments that physicians can apply to optimize the health of their patients. Fellowship course details and objectives include:
• A detailed program offering hands-on experience in stem cell characterization and laboratory applications
• An opportunity to learn cell culture processes including plating, trypsinization, harvesting, and cryopreservation
• Gaining the ability to understand and apply quality control tests including cell count, viability, flow cytometry, endotoxin, mycoplasma, and sterility
• Learning to perform CGMP functions including clean room maintenance, gowning, and environmental monitoring
• Establishing insight on relevant applications of stem cell processing and regulations that apply to a certified facility
• Receiving the tools necessary to implement regulatory and clinical guidelines when setting up a GMP facility
• Providing participants with copies of presentations, procedural protocols, and all forms associated with a GMP facility, as well as case books and full protocols for approximately 30 indications
• Demonstrating the ability to perform clinical procedures including lipoaspirate and bone marrow isolation, and reintroduction of stem cells for various indications
The new ISSCA stem cell training web page also features an informative blog that publishes four new articles in the field of regenerative medicine weekly.
To learn more, visit the ISSCA stem cell training web page, email email@example.com, or call 305-560-5337.
The International Society for Stem Cell Application (ISSCA) is a multidisciplinary community of scientists and physicians, all of whom aspire to treat diseases and lessen human suffering through advances in science, technology and the practice of regenerative medicine. ISSCA serves its members through advancements made in the specialty of regenerative medicine.
The ISSCA’s vision is to take a leadership position in promoting excellence and setting standards in the regenerative medicine fields of publication, research, education, training, and certification.
As a medical specialty, regenerative medicine standards and certifications are essential, which is why ISSCA offers certification training in cities all over the world. The goal is to encourage more physicians to practice regenerative medicine and make it available to benefit patients both nationally and globally. Incorporated under the Republic of Korea as a non-profit entity, ISSCA is focused on promoting excellence and standards in the field of regenerative medicine.
Stem cell training web page launch