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Can Hip Replacements Be Obsolete Through The Use Of Stem Cell Therapy?

As more and more doctors train to be proficient in stem cell therapy, many are seeking to increase their revenues, as well as expand their practices. As a result of this, Adimarket is hoping to fulfill the needs of the doctors and to help their patients in the most efficient way possible. However, there are other goals that we have as well. We hope that one day, PRP and Stem-cell therapies will replace certain medical procedures, making them more effective and more convenience. One of these procedures we hope to eliminate are hip replacements.

 

Natural tissue regeneration has been something that many scientists have have been focusing on for years. One of the main focuses have been in orthopedics, or the study of bones and muscles. Utilizing the stem cells of a patient in order to regrow or replace cartilage can be a godsend for treatments involving conditions such as osteoarthritis as well as sports and other injuries. Many wonder that, if we can heal muscle and joint damage utilizing PRP and stem-cell therapy, exactly much can we potentially heal?

 

It may be a possibility in the near future, based on the current evidence, to consider the use of PRP and stem-cell therapy over hip replacement surgery. A 2016 study published in the Proceedings of the National Academy of Sciences showed that had stem cells successfully grow on an artificial hip joint. They even create a therapy that, combined with the stem cells, could lower the risk of recurrence when it comes to arthritis in the joint.

 

What Treatments Are We Already Utilizing?

 

While seeing hip replacements become a thing of the past is a potential occurrence in the near future, the science is not that far yet. Adimarket is working to provide the tools necessary to utilize both PRP and Stem Cell therapy in treating sports injuries, wounds, and orthopedic applications.

 

In fact, the two therapies are in no way mutually exclusive. In many cases, both PRP and stem cell therapies can be utilized at the same time, so long as the stem cells come from the patient themselves. Doing this helps to reduce the risk of rejection.

 

PRP can be extracted from the blood, and the stem cells can easily come from either using bone marrow, or fat tissue. This is then injected directly into the treatment site, and then we simply wait for the magic to happen.

 

Adimarket Has Got You Covered

 

If you are a doctor or own your own practice, then we urge you to consider adding PRP and stem cell therapies to your treatment options. Adimarket provides a great deal of technology and equipment that is designed to give patients the best experience and treatment possible.

 

Our equipment is some of the best in the trade. We can provide fast and reliable processing of platelets that is able to concentrate the blood platelets up to 16 times. If you are interested to know more about it or to provide this equipment in your own practice, consider looking up Adimarket.

Will we ever see hip replacement surgery become obsolete? Possibly. It is our hope that it does. However, we are hoping that until then, we can provide the necessary technology to help doctors provide the best stem cell and PRP treatment to their patients.

How PRP can Assist With Wound Healing

PRP Therapy, otherwise known as Platelet-rich Plasma Therapy, if often performed by doctors after a surgery, as it helps surgical wounds to heal quicker and better. There are many ways in which this therapy can be used, including orthopedic and aesthetic applications.

 

Not all of us reading this are medical doctors or researchers. Because of such, we at Adimarket believe that breaking down the core aspects of how PRP therapy could help in wound healing would be beneficial.

 

How Does A Wound Heal?

 

Whether it is a paper cut or a severe gash, all wounds have a process of healing and goes through stages. This begins with bleeding. Although not all wounds bleed, even if they don’t follow this phase, they will still follow the rest of them.

 

During the bleeding process, platelets in the blood bound together, which forms clots. This stops the bleeding and helps the wound to begin healing by closing the wound with what is called a scab. Afterwards, swelling starts to occur. This is due to the immune system working to send white blood cells and nutrients to the source of the wound, which helps to fight off infection. During this time, it is not uncommon to see a clear liquid around the wound, which is mean to keep the area clean and prevent further intrusion by microorganisms.

 

For weeks after, a variety of factors and body processes, such as oxygen, nutrients, and red blood cells, work to create new skin tissue, which permanently replaces the tissue that was damaged or removed. This includes collagen, which is the material that binds together and forms the new skin tissue.

 

This tissue regeneration is the last stage of wound healing. The time it takes for the new skin tissue to fully form depends on the severity of the wound, taking as little as a week for smaller wounds, to many weeks for much deeper wounds or gashes.

 

How PRP Promotes Healing.

 

So now that you know how wound healing works, it should be easier to understand why and how PRP therapy can be effective. Platelet-rich Plasma is exactly what it sounds like, it is blood plasma that has a very high concentration of platelets and other things, such as growth factors. However, PRP is often found at much higher concentrations than what is typically seen in blood. As with our case at Adimarket, it can be up to 10 times higher.

 

Other things can be found like this PRP as well, such as epidermal growth factor, fibroblast growth factor, and connective tissue growth factor, these are three of the many growth factors that the body uses as a natural healing aid. The way that PRP can help with wound healing is when it is injected into the wound itself. This basically supercharges the healing process, and helps the healing process go more quickly, and more smoothly.

 

This is because PRP provides the body with oxygen, platelets, and nutrients that the body can use right away. This also lowers both the risk of infection, and prevents scarring, which can be unsightly for many. Many doctors have been using PRP for a long time, and utilize them for patients because it is effective.

How Arthritis Can Be Alleviated With PRP Treatments

At Stem Cells Training , we often get asked a lot of questions about the efficacy of PRP, or Platelet-Rich plasma and Stem Cell treatments. Especially as they pertain to disorders like arthritis. When it comes to arthritis, many doctors understand how broad of a term that it can be. It can include a wide variety of different disorders and diseases with many causes. However, it is good to note that PRP therapy may not work for all causes of arthritis.

 

It is vital to point out when regenerative medicine is an appropriate alternative to traditional medicine for arthritis and when not.  This is important so that patients do not pay for treatments that may be ineffective or untested. This helps to pair the appropriate treatment options to the right patient.

 

Osteoarthritis treatments and PRP

Osteoarthritis is the most common form of arthritic. The way it effects your mobility occurs when cartilage, which prevents joints from causing friction,  breaks down over time. This can result in many symptoms, including swelling, and sharp main when you move your joints. This is often correlated with age and growing old.

These therapies have been used for awhile as an effective way to treat osteoarthritis, and even reverse it. PRP treatments, for instance, inject material into the joint, which causes the body to have a biological response. This response helps the body to form new cartilage, which can reduce inflammation and slow down the progression of the disorder.

 

Is Rheumatoid Arthritis Treatable by PRP?

Rheumatoid Arthritis is an immunological disease, and isn’t the cause the normal wear of the cartilage  over time. It is a common form of arthritis, but not as common as osteoarthritis. Rheumatoid Arthritis is when one experiences joint pain due to the fact that the body’s immune system is attacking the tissues in their own joints.

While regenerative medicine treatments like PRP can be effective in reducing pain and damage from the progression of the disease, it is not the first choice. However, regenerative medicine cannot fully treat the immune system and the damage that it can cause.

What about Fibromyalgia?

Although not technically arthritis, Fibromyalgia is often associated with the joint disorder. This is due to the fact that it can cause joint pain. This is due to the miscommunication between the brain and spinal cord, which can make you feel pain even when no cause is present. This may be the result of an overactive nervous system, which causes the body to experience pain.

Due to it having little to nothing to do with the joints, little can be done to help the condition where PRP and stem cell therapies are involved. Patients who want relief from their pain will have to look elsewhere. Other more proven treatments include prescription medications, physical therapy, and muscle relaxants.

 

While it cannot be used for every condition and every type of pain out there, PRP does hold potential. It is used to effectively treat chronic pain and deterioration due to osteoarthritis and orthopedic type injuries. This can be a great alternative for people who are looking for alternatives to traditional treatments, such as medications for pain, as well as surgery. However, it is best to check out the evidence for yourself, and not just take our word for it.

The top five components of amniotic fluid stem cell therapy

Now stem cell therapy for bone and joint conditions is now mainstream. There are plenty of small to medium size studies which show the effectiveness of the treatment. And amniotic fluid has been great for treatment for a few reasons. One is that it’s readily available. There are women every day undergoing a scheduled C-section who are willing to donate their amniotic fluid to help other people. The baby’s fine, there’s no ethical considerations. So there’s no shortage of supply. Secondly, it has so much great stuff in it and there’s no rejection reaction when you take Betty’s amniotic fluid and process it and then inject it into John. So here are the top five components.

Number one is that there are a lot of growth factors in amniotic fluid. Well, what exactly is a growth factor? A growth factor is a natural substance that’s produced by the body that helps to promote repair and regeneration of your tissues. And it also signals to other cells to help differentiate and promote repair and regeneration as well. So it does it itself, but it also recruits some friends to help out. There are about 70 to 80 growth factors in amniotic fluid that help with all of this repair and regeneration, which is very helpful for not only the baby, that it’s around, but also when it gets harvested and processed and injected into those who need it for say knee arthritis, it’s very effective as well.

The second component that’s very important of amniotic fluid is hyaluronic acid. Now hyaluronic acid is a substance that is extremely prevalent throughout our bodies, it’s a medical carbohydrate that is in liquid form that helps to lubricate, cushion and protect your joints. And also your eye. And it’s also in cartilage. And it’s also in some other tissues. But basically we talk about it in the knee joint for example, it’s like the motor oil of your knee joint. Okay, so when it comes from the amniotic fluid, and injected it’s just another beneficial effect of a substance going in. It’s also the main substance in something like Synvisc or Hyalgan, treatment known as viscose supplementation.

The next component of amniotic fluid is something called cytokines. Cytokines are small proteins that are released by cells that are great communicators. They don’t do a lot by themselves, but they basically communicate between other cells in the body to create the interaction that’s going to promote repair and regeneration. So some people use the term growth factor and cytokine interchangeably. There are differences between them. But keep in mind that cytokines there’s a ton of them in amniotic fluid and they have very fancy names, like vegeff and TNF. But what they do is they communicate between other cells. So for instance if you inject them into a knee joint, there going to help communicate between cells and help recruit cells from around the body to come and help repair and regenerate the damage in your knee.


Now the fourth component of amniotic fluid are anti-microbial factors. Now there’s no need to go through the specific scientific names of them but think about it like this, when the amniotic fluid surrounds the baby, it does a lot of different functions. But one of them, it helps prevent infection from occurring in the baby. All right, so when you inject it into the knee or elbow or whatnot, it has some of the same effect by helping to prevent infection. And that’s very helpful because the rate of infection with an amniotic fluid injection is really, really, really low. It’s not negligible, but it’s really low.

The fifth component of amniotic fluid and I saved the best for last, are stem cells. What exactly is a stem cell? A stem cell is a blank slate. It’s a master cell of the human body that has the ability to differentiate into most of the 200 or so different cell types in the human body. Now there’s different types of stem cells. One is embryonic. An embryonic cell can differentiate into any type of the human body. The problem with embryonic is that it often doesn’t know when to stop. So studies in the past have looked at embryonic cells, for instance in baboons, they put them into the discs of baboons, looking at disc degeneration. The problem is a lot of those baboons developed tumors.

So they stopped the study and embryonic cells are not used, they’re not present in amniotic fluid. What’s present in amniotic fluid are what’s called pluripotent stem cells and those cells are able to differentiate into most of the different cell types in the human body and all of the ones that are pertinent to what it’s being used for commercially, such as cartilage, skin, bone, muscle, tendon, ligament, da da da da da. So it’s very, very effective. It’s also able to differentiate into the cells that are important in kidney, lung, liver, and on down with organs. Cardiac. So there’s a lot of usage going on systemically as well as locally with injection.

So those are the top five components of amniotic fluid. One more, actually two more quick points. One is that there’s no rejection of amniotic fluid from one individual to another. I mentioned that but I wanted to point it out one more time because we get that question all the time. The second point is that a lot of people think that when you undergo a regenerative medicine procedure that it’s the stem cells doing, carrying the heavy load, doing the heavy lifting with the repair and regeneration. That is actually only partially true. What’s really doing most of the work are the growth factors. Growth factors are the ones that are pulling in the body’s own stem cells and then also directly mitigating the repair and the regeneration. So the stem cells are only part of the equation, keep that in mind.


Why Should you Utilize PRP Therapy

Our Company Adimarket obviously promotes Stem Cell and PRP (Platelet-rich plasma) therapy, which is why we are OK with providing the technology to doctors all around the world. The reason why we do it is because we believe that regenerative medicine is the future of medicine. In this articles we want to help you and persuade you to give stem cell and PRP technology a chance.

 

Why these two? Well, there are a plethora of reasons why you should provide these treatments to your patients. However, the one main reason is due to the projected growth of the technology. It is expected to grow between 9.6% to 12% in the next five years alone. This can make the market value for the technology upwards of $420 million.

 

However, this is not something that we believes should be motivated by money, or at least not only about money. We agree that money is a motivating factor for any practice or business venture, but also the market shows a 12% increase in demand for regenerative treatments. This shows that the current system of treating symptoms and not the underlying cause is not satisfactory for the patients.

 

An Alternative?

 

This technology is on the rise, and many people consider it a viable replacement for conventional medical practices. This can potentially treat, if not cure many diseases, such as injuries, osteoarthritis, and other musculoskeletal issues that can result in chronic and long term pain.

 

Baseball pitchers often have to deal with chronic elbow pain as a result of long term stress of the ligaments and muscles. Many choose to find relief in surgery, as they want to be able to continue playing their dream career. However, so many more players are opting for PRP therapy instead. This has to potential to treat all kinds of sports-related injuries, including from football, soccer, and even tennis. Many people from all walks of life are seeing PRP therapy as a viable alternative.

 

This rings true even if you are not an athlete. Many people suffer from chronic pain due to arthritis or from a previous work injury, and as a result are turning to this therapy in order to cut down on pain medications, and to treat the issue, and not just mask it with pills. PRP has skyrocketed in popularity among all demographics.

 

What about hair loss?

 

When it comes to PRP therapy, it has other uses outside of just osteoarthritis. One popular application for the treatment would be alopecia, or hair loss. Another would be facial rejuvenation. With Alopecia, PRP therapy can be a more reliable and less painful alternative to hair transplants and topical solutions. These solutions can be short lived or even ineffective, which makes PRP therapy a much more trustworthy alternative for testing.

 

This means that the prospects of PRP therapy over the next 5 years is good. This is widely due to ever-increasing availability, as well as the high demand for the process. People see that these therapies are not only effective, but worthwhile, and they want them to stay.

 

That said, very few insurance companies will cover regenerative medical procedures, assuming that any at all cover it. This means that the client is footing the bill, and paying for the procedure out of pocket. So the people who are increasing the demand for the therapy are willing to pay for it out of pocket due to trust that it works.

 

This allows you to open the door to give alternative treatments for the patients that request it, as well as increase your bottom line in the same breath. Also, at least until insurance companies come on board, you can earn the full price of your services. I don’t think anymore needs to be said.

Bone and Tissue Regeneration A Game Changer

British researchers at the University of Birmingham conducted a study that could alter the field of regenerative medicine. They developed a way to regenerate human bone and tissue using non-scale structures. This helps the body more efficiently replace tissue that was lost. Although it will be many years before the technology is approved for public use, the implications of the research can significantly alter the use the stem cell therapy.

 

Global Stem Cells Group offers not only equipment and kits for point of care stem cell applications,  but also through Stem Cells Training Inc  we provide physicians with  Hands-on Stem cell training, designed for those who wants to get involved in this exciting field of medicine. Degenerative conditions could be better treated through the use of the stem cell technology.. To better understand what this technology entails, we will use Osteoarthritis as a prime example.

 

In case you were unaware, osteoarthritis is a condition where the tissue between the joints start to degrade, which prevents the free movement of the joints. This can cause severe pain in sufferers of the condition. To help relieve the pain, the doctors attending our courses are taught to use the equipments for  PRP and Adipose derived stem cells isolation and processing. The use of this technology can help to reverse some of the effects, lower pain and allows for more movement.

 

What was discovered

 

It was discovered by the researchers that these nano-structures could be produced naturally through the stimulation of human cells, these structures are known as vesicles. Vesicles are small extracellular structures that can have a multitude of functions, such as helping cells to create certain substances.  

 

Researchers came to the conclusion that “purifying” these vesicles could make a substance that can be highly beneficial in regenerative medicine. This could be use to further create new growth tissue. The efforts were focused on making a tissue that can be used in more than one patient, other than the more autologous method that current doctors are trained in.

 

This Autologous treatment is when you take the stem cells from the patient who is currently being treated. That is then injected into where the treatment is occurring. This currently treatment method lowers rejection rates, but each treatment needs new stem cells. The researchers at the University of Birmingham are trying a new approach.

 

They wanted to go further, and create a treatment that any patient can use. They believe that vesicles are important in this process, and they showed that they can be used to regenerate tissue regardless of the initial owner of the cells. This way, it increases the potential for just one sample can be used to treat multiple people at once.

 

Why it matters

 

Regardless of the criticisms of stem cell research, the research continues which allows us to further train our doctors. This excites us, as we strive to teach the best and most effective methods for our patients. This helps us treat the countless patients that we have treated or have helped treat. We are also excited for the great strides in medical research, which helps people all around the world to seek treatment for a variety of ailments.

 

Regenerative medicine has great potential. It can alter the landscape of modern healthcare and redirect it away from an era that is too used to using surgery and medications to treat every ailment. This makes regenerative medicine a great alternative that will help treat patients and help them to cure their diseases, instead of just managing their symptoms.

 

Hopefully this research will prove to be effective, and be able to be used for a whole swath of diseases, thus eliminating the need for various surgeries. This can also help reduce the number of pharmaceuticals on the market as well. We will see in time this treatment can help us to create whole tissue in the lab.

IFATS Recommendations for FDA Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products

International Federation of Adipose Therapeutics and Sciences (IFATS)

45 Lyme Road – Suite 304

Hanover, NH 03755 USA

Tel: 1-603-643-2325, Fax: 1-603-643-1444

 

September 26, 2016

 

Division of Dockets Management (HFA–305) Food and Drug Administration

5630 Fishers Lane, Rm. 1061

Rockville, MD 20852

 

Re: FDA-2014-D-1856 – Comments to 2014-2015 Draft Guidance regarding:

  • Docket FDA-2014-D-1584: “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Draft Guidance for Industry”;
  • Docket FDA-2014-D-1696: “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and Food and Drug Administration Staff”;
  • Docket FDA-2014-D-1856: “Human Cells, Tissues, and Cellular and Tissue-Based Products from Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry”;
  • Docket FDA-2015-D-3581: “Homologous Use of Human Cells, Tissues, and Cellular and Tissue- Based Products; Draft Guidance for Industry and FDA Staff.”

 

Dear Sirs and Madams:

The International Federation of Adipose Therapeutics and Sciences (IFATS) appreciates this opportunity to submit the following comments to supplement its earlier written comments and recent testimony at the September 12-13, 2016 Public Hearing on the 2014-2015 Draft HCT/P Guidances concerning: a) Minimal Manipulation; b) Same Surgical Procedure; c) Adipose Tissue; and d) Homologous Use.

IFATS is committed to the responsible advance of the science and translation of new adipose therapies, and it is determined to ensure patient safety. It was founded in 2003 by pioneering adipose stem cell biologists and clinician–scientists with the goal of advancing the science of adipose tissue biology and its clinical translation to therapeutic applications. Since that time, IFATS has remained at the forefront of regenerative medical applications involving adipose tissue and cells. Membership now spans 40 countries in North America, Europe, Africa, the Middle East, Asia, Australia, and Central and South America, and includes basic scientists, translational researchers, clinicians, and regulatory and biotech representatives. IFATS is formally aligned with, and its members serve on the editorial boards of the prestigious journals, Stem Cells and Stem Cells Translational Medicine. With the International Society for Cellular Therapy (ISCT), IFATS has provided the scientific community with a detailed description and definition of adipose derived cells (both stromal vascular fraction, or SVF, and adipose-derived stromal/stem cells, or ASCs) in the formal publication entitled Cytotherapy. Thus, IFATS possesses the necessary expertise to assist regulatory agencies in understanding adipose tissue, and regulating the safety and efficacy of adipose-related products and therapies.

Drawing on this expertise, IFATS has reviewed the 4 draft guidances with great care. It respectfully requests the FDA to reconsider and modify the 4 draft HCT/P guidances as follows:
Recommendation #1 – Cell-Based Risks: Interpret and evaluate an HCT/P’s homologous use and minimal manipulation based on its manufacturer’s intended use in the patient.

 Recommendation  #2  –  Provider-Based  Risks:  Reduce  provider-created  risks  by  targeting provider behavior.

 Recommendation #3: Recognize that adipose HCT/Ps have both structural and nonstructural functions, and regulate based on its manufacturer’s intended use in the patient.

 Recommendation #4: Revise the evaluation of minimal manipulation and homologous use as they pertain to particular applications of adipose tissue.

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IFATS recognizes the FDA’s challenge in developing regulations that fulfill the agency’s dual and interrelated responsibilities of protecting patients while promoting innovation. IFATS further recognizes that although these are complementary rather than competing objectives, they are often difficult to pursue simultaneously. The FDA’s 3-tiered, risk-based §§ 361 – 351 framework balances these concerns by making the degree of regulatory oversight proportionate to the degree of an HCT/P therapy’s risk.

The concepts of homologous use and minimal manipulation are key determinants of whether an HCT/P will be classified as a § 361 product (which does not need premarket approval) or a § 351 drug, device and/or biological product (which requires formal premarket approval). The applicability of § 351’s “same surgical procedure” exception also turns on homologous use and minimal manipulation. For most manufacturer-clinicians, § 351 categorization raises insurmountable obstacles due to the time and expense of obtaining premarket approval. In such cases, § 351 classification effectively prohibits access to safe and effective HCT/P therapies, even when those therapies involve a patient’s own cells and/or can deliver superior results with reduced risks. At the same time, § 351 oversight is essential for therapies that pose greater risks due the HCT/P’s characteristics, mechanism(s) of action and circumstances of use.

A second type of risk involves rogue clinicians offering false promise in the form of unproven therapies performed with few safeguards and less training.  Provider misconduct is not unique to HCT/P therapies; it pervades all areas of medical practice. Nevertheless, IFATS shares the FDA’s alarm over such practices in the context of HCT/Ps, and is equally determined to curtail them. Because a solution cannot solve a problem without identifying and attacking its root cause, effective regulation of HCT/P-related risks must recognize and respond to their multivariate causes. Put simply:

  • Sections 351 and 361 appropriately attempt to regulate HCT/P therapies proportionate to the risks of unpredictable and/or unsafe cell behavior.
  • However, the risks of untrained providers misusing HCT/P therapies are caused by providers misbehaving, not cells misbehaving.

 Consequently, interpretive guidance that restricts the definition and application of HCT/P terminology can only go so far in restricting provider-based risks. In addition, restrictive, inaccurate or imprecise definitions and interpretations carry their own risks of restricting access to therapies and restricting a patient’s right to evaluate risk through the process of informed consent.

Therefore, IFATS recommends that the FDA adopt an overall two-part strategy that focuses on both categories of HCT/P risks, i.e., those relating to cell behavior and those that pertain to provider behavior.

Recommendation #1 Cell-Based Risks:

Interpret and evaluate an HCT/P’s homologous use and minimal manipulation based on its manufacturer’s intended use in the patient. Interpretive guidance should predicate each definition on to the functions and/or characteristics of the specific composition (i.e., cell type(s) and/or matrix or other component(s)) that are involved in, and/or relevant to the manufacturer- clinician’s intended use in the patient.

Recommendation #2 – Provider-Based Risks:

To reduce provider-created risks, the FDA should target provider behavior by collaborating with IFATS and comparable organizations to draw on and supplement existing federal and state methods of certification, registration, and similar measures.

Adopting this two-part strategy can control risk more comprehensively – and therefore more effectively – in furtherance of the FDA’s dual and interrelated obligations of protecting patients and promoting the availability of HCT/P therapies.  IFATS explains each recommendation as follows:
Recommendation #1 – Cell-Based Risks: Interpret and evaluate an HCT/P’s homologous use and minimal manipulation based on its manufacturer’s intended use in the patient.

 The four draft guidances on homologous use, minimal manipulation, same surgical procedure and adipose tissue individually and collectively intend to “improve stakeholders’ understanding” of 21 CFR 1271 by clarifying the FDA’s interpretation of homologous use and minimal manipulation. As demonstrated by the initial round of public comments and the ensuing public hearing on September 12 and 13, 2016, the draft guidance documents have not clarified applicable regulations. They have instead compounded the difficulty of understanding and complying with them. The drafts’ introduction of new definitional inaccuracies has also amplified rather than reduce patient risk.

IFATS respectfully requests the agency to clarify the definitions and application of homologous use and minimal manipulation by interpreting each as referring to the characteristics of the specific cell type(s) and/or the matrix or other component(s) that are involved in, and/or relevant to the manufacturer’s intended use in the patient. Thus, the definition of homologous use with interpretive guidance would read as follows:

21 CFR 1271.3(c): Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.
Recommended GUIDANCE: As used in this section, “performs the same basic function or functions in the recipient as in the donor” shall be interpreted as referring to one or more of the function(s) of the specific composition of the therapeutic/product, reflecting the specific cell type(s) and/or the specific matrix or other component(s) in the donor tissue that are involved in, and/or relevant to the manufacturer’s intended use in the patient.

 Similarly, the definition of minimal manipulation with interpretive guidance would read as follows:

21 CFR 1271.3(f)   Minimal manipulation means:

  •  For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement;
  • For cells  or  nonstructural  tissues,  processing  that  does  not  alter  the  relevant  biological characteristics of cells or

Recommended GUIDANCE: As used in this section, “relevant” characteristics shall be interpreted to mean the characteristics of the specific cell type(s) and/or the specific matrix or other component(s) in the donor tissue that are involved in, and/or relevant to the manufacturer’s intended use in the patient.

 Rationale: Incorporating and relying on the manufacturer’s intended use harmonizes the interpretation and definition of homologous use and minimal manipulation with statutory directives to predicate the regulation of drugs, devices and biologics on the manufacturer’s intended use.

Defining relevant characteristics in terms of “the characteristics of specific cell type(s) and/or the matrix or other component(s) in the donor tissue that are involved in, and/or relevant to the manufacturer’s intended use in the patient” promotes patient safety by insisting on a reasonable and scientifically supportable rationale for using an HCT/P for a particular mechanism of action. This clarification balances the FDA’s dual responsibilities of protecting patients from undue safety risks while promoting the ongoing availability and continued development of HCT/P therapies.

Example of Non-Homologous Use: Decellularized adipose matrix used to accomplish the manufacturer’s intended use of a particular metabolic or systemic effect in the patient (e.g., reducing insulin levels in a diabetic patient) is non-homologous because decellularized matrix is not relevant to metabolic or systemic activity.

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Recommendation #2 – Provider-Based Risks: To reduce provider-created risks, the FDA should target provider behavior by collaborating with IFATS and comparable organizations to draw on, and supplement existing federal and state methods of certification, registration, and similar measures.

For a risk-reduction strategy to succeed, it must target the root cause of the risk. Revising, retracting or replacing interpretations of regulatory terminology can target the risks of cells behaving in an unsafe ways, but can do little to prevent providers from behaving in unsafe ways. Because the risks of irresponsible providers offering unsafe treatments are not exclusive to HCT/P therapies, many federal and state mechanisms already exist for identifying, disciplining and prohibiting clinics and clinicians from endangering patients.

IFATS shares the FDA’s concern about provider-related risks in the HCT/P sector and shares its determination to end or minimize these risks. IFATS respectfully requests the FDA to collaborate with it and comparable organizations to identify and draw on existing federal and state methods for curtailing provider misconduct, and developing additional protections in the form of provider certification, registration, monitoring and similar measures. At present, the §§ 351-361 regulatory framework does not – and cannot – adequately respond to this form of risk. Collaboration among stakeholders and coordination with existing means of provider oversight offers the most effective and efficient strategy for protecting patients from provider-created risk.

Therefore, IFATS respectfully requests the FDA to meet with IFATS, the American Association of Blood Banks and other accreditation bodies for the purpose of working together to identify provider-focused safety objectives and measures that can be translated into formal accreditation requirements and interpretive guidance.

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Recommendation #3: Recognize that adipose HCT/Ps have both structural and nonstructural functions, and regulate based on its manufacturer’s intended use in the patient.

 IFATS requests the FDA to expand its definition of adipose tissue from exclusively structural in function to include both structural and/or nonstructural functions, depending on the manufacturer’s intended use in  the patient. This modification is critically necessary in order to:

  1. Reconcile the  interpretive  guidance  on  the  definition  and  regulation  of  adipose  with applicable statutory and regulatory requirements;
  2. Reflect and ensure biological accuracy; and most importantly,
  3. Regulate an HCT/P’s risks based on the manufacturer’s intended use and mechanisms of action in the patient.

More specifically:
a.      Recognizing adipose tissue’s structural and/or nonstructural functions is required by applicable statutory and regulatory requirements.

 Adipose HCT/Ps must be defined as having structural and/or nonstructural functions to align the draft guidance with statutory and regulatory recognition that cells and tissues may have more  than  one function. According to 42 USC § 321(g)(1), “[t]he term ‘drug’ means … (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). (emphasis added). Statutory directives to focus on intended use pervade FDA regulation, including the regulation of drugs, biologics, devices, cosmetics, pesticides and more. Applicable statutes and regulations explicitly and implicitly recognize that the human body is complex, and its tissues and cells are often versatile and multi-functional. For example, 21 CFR 1271.3(c)’s definition of homologous use correctly recognizes that an HCT/P may have more than one “basic function.” It never says or even suggests that an HCT/P can only have one function, or that the regulator has sole authority to define that function and thereby dictate a manufacturer’s intended use. And yet the draft guidances do just that by insisting that adipose HCT/Ps are solely structural.

To align interpretive guidance with the regulations and statutory provisions being interpreted, IFATS respectfully requests the FDA to avoid pre-determining specific functions and uses for specific HCT/Ps. Instead, it should base regulations and guidance on the HCT/P’s function(s) and characteristic(s) that are relevant to its intended use by the manufacturer.
b.      Recognizing adipose tissue’s structural and/or nonstructural functions is necessary to correct factual inaccuracy.

 Regulation 21 CFR 1271.10(a)(4) categorizes an HCT/P as “either” structural or nonstructural, depending on its function. A structural HCT/P “does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function.” A nonstructural HCT/P “has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function.”

The draft adipose guidance expressly acknowledges that adipose tissue contains adipocytes, preadipocytes, fibroblasts, vascular endothelial cells, a variety of immune cells, and also stores energy in the form of lipids. Citing only Junqueira ’s Basic Histology: Text & Atlas , the draft guidance classifies adipose as a connective and therefore structural tissue. This result is internally inconsistent and factually inaccurate – and the FDA’s sole cited authority explains why.

Junqueira classifies connective tissue as: 1) connective tissue proper; 2) embryonic connective tissues; and 3) specialized connective tissues. The latter category defines specialized connective based on their principal specialized functions. Blood, reticular connective tissue, adipose tissue, bone and cartilage all qualify as specialized connective tissues with specialized, nonstructural functions. Junqueira ’s examples include the following:

  • Blood is a specialized connective tissue; its principal function of transport is nonstructural.
  • Reticular connective tissues include the liver, pancreas, bone marrow and lymph They are nonstructural tissues because their principal functions are metabolic, including endocrine.
  • According to Junqueira – the FDA’s sole cited authority adipose tissue is nonstructural specialized connective tissue; its primary function is metabolic with co-existing structural

Junqueira ’s categorization of adipose as primarily nonstructural reflects longstanding scientific consensus. In1893, Gustav Neuber described his use of fat grafting in the orbital region to heal the adherent scarring which was the sequela of osteomyelitis. As a result of its nonstructural healing functions, the fat graft transformed facial scarring to more normal appearing skin and subcutaneous tissues. [6] In 1912, Holländer described the successful use of fat injections to prevent the recurrence of scarring following breast surgery. [7] In 1926, Charles Conrad Miller developed a new system for injecting fat grafts, and described 36 cases of correcting cicatricial contraction on the face and neck, and reported “excellent results” for another 2 cases after using fat grafts to treat “very persistent parotid fistulas…which defied all other methods of treatment.” [8] These and similarly favorable outcomes resulted from fat’s transformational nonstructural repair of the tissues into which it was placed. [8]

The understanding of the diverse roles of adipose tissue has steadily expanded [9], due in large part to the discovery of the first widely accepted adipokine, leptin, in the mid-1990’s. [10] Adipose tissue secretes proteins with systemic actions on hematopoietic, reproductive, metabolic, and other cells and tissues demonstrates unequivocally that adipose meets the definition of a true “endocrine” organ.[11,12] A Google scholar search of all available online medical and research databases for “the primary function of Adipose Tissue” returns 538,000 journal articles. Although the search did not designate a  specific function, the search results referred to adipose tissue almost exclusively as a nonstructural metabolic and endocrine organ with secretory properties. A search for an exact match of the phrase “primary function of adipose tissue” yielded the following: “It was long believed the primary function of adipose tissue was energy storage; in fact, stromal adipose is a complicated endocrine organ.” However, even energy storage is nonstructural.

The FDA’s draft guidance on minimal manipulation defines nonstructural tissues as “serv[ing] predominantly metabolic or other biochemical roles in the body such as hematopoietic, immune, and endocrine functions.” To illustrate, the draft guidance offers “cord blood, lymph nodes, pancreatic tissue” as examples of nonstructural tissue. These tissues are indeed nonstructural – but they are also specialized connective tissue, as explained in Junqueira. In addition adipose has “hematopoietic, immune, and endocrine functions,” as explained below. As demonstrated by Junqueira, adipose HCT/Ps clearly do more than “reconstruction, repair, or replacement that relate to its utility to cushion and support the other tissues in the subcutaneous layer (subcutaneum) and skin.And the FDA’s own nonstructural examples prove that classifying connective tissue, including adipose tissue as solely structural is factually inaccurate and logically flawed.

 Thus, IFATS strongly recommends that the draft guidances be revised to define and categorize adipose tissue has both structural and nonstructural functions.

In support, IFATS offers the following examples of adipose’s nonstructural, and combined nonstructural and structural functions.
Nonstructural Functions of Adipose HCT/Ps:

  1.  Nonstructural Endocrine Functions – It is well recognized that adipose is an endocrine organ which, like other endocrine organs, performs a variety of nonstructural Adipose tissue secretes proteins with nonstructural, systemic actions on hematopoietic, reproductive, metabolic, and other cells and tissues. [11, 12]

Examples:

  • Glucose and lipid metabolism control via adipokine secretion [13]
  • Reproductive and endocrine control via adipokine secretion [14-16]
  • Immunomodulatory and immunosuppressive systemic control via cytokine and protein factor secretion [17-22]

2.      Nonstructural Paracrine Functions

  • Angiogenic control via vasculogenic cytokine secretion [22-26]
  • Hematopoietic control via cytokine secretion, both locally and systemically [27]
  • Neurogenesis via secretion of cytokine factors [28-34]

3.  Nonstructural Hematopietic Potential of adipose stem cells in adipose deposits

  • Reservoir for hematopoietic and lymphoid progenitor cells similar to bone marrow [18, 35, 36]
  • Thermogenesis (brown and beige fat)[37-41]
  • Energy reservoir (white adipose depots) [42,43]

4.      Nonstructural Promotion of Lactation

  • Fat serves as an energy reservoir and nutrient supply for breast epithelial cells.
  • As pregnancy progresses, the breast epithelium proliferates in a branching manner to occupy the majority of the adjacent adipose tissue and
  • At parturition, the epithelial cells draw on the lipid reserves of adipocytes within immediate proximity and secrete these nutrients into the milk available to the newborn infant during
  • As long as the mother continues to breast feed the infant, the epithelial cells remain viable and
  • If suckling is discontinued for periods of 24 to 48 hours, the epithelial cells undergo rapid apoptosis, leaving pre-adipocytes and adipocytes as the predominant cell within the breast
  • While the presence and organization of epithelial cells within the breast tissue provide it with a unique architecture, the mammary adipocytes themselves show remarkable similarity to adipocytes from elsewhere in the Thus, the mammary fat pad displays homology to other adipose tissue depots.[44]

5.      Nonstructural Regenerative Functions

  • Local and circulating multipotent progenitor cells can repair and regenerate damaged tissues such as repairing irradiated skin, alleviating fibrotic changes, improving mobility and vitality, and repairing structures such as hair follicles and [45-47]. Specific examples include:
    • Modulation of scarring
    • Treatingold burn scars [55-57]
    • Release of adherent scarring/fasciotomies [58]
    • Modulation of scarring in primary cleft lip repair [59]
  • Multipotent progenitor cells may be recruited for repair and regeneration of ischemic damage induced by acute myocardial infarction. [48]
  • Adipose mesenchymal stem cells as progenitor cells in a perivascular position contribute to vascular network formation and vascular structures.[49-52] As such, the adipose mesenchymal stem cells are located in a position and serve a role shared by mesenchymal stem cells located in nearly all body tissues [53]. Adipose MSCs located in a range of tissues can enhance vascularity and perfusion, and thus provide cells that are precisely homologous to those already present in the
  • Adipose mesenchymal stem cells induce a monocyte/macrophage phenotype switch from M1 to M2 macrophages, contributing to improved infarct healing post-acute myocardial [54]

6.  Nonstructural Functions in Bone Marrow – Bone marrow and blood products are exempt from regulation under § 351 and 361. For over 40 years, it has been clearly established that adipose is present in bone marrow where it serves a wide variety of nonstructural functions. The following physiologic processes have nothing to do with providing cushioning and support and therefore are not properly categorized as a structural use or function of adipose cells. [3]

  • Pre-adipocytes as mesenchymal cells in bone marrow: Bone marrow contains a spectrum of mesenchymal cells, including pre-adipocytes that can perform the nonstructural function of differentiating into adipocytes, osteoblasts and chondrocytes depending on the organism’s current needs.
  • Pre-adipocytes and adipocytes regulate lympho-hematopoiesis and enable the bone marrow microenvironment to regulate proliferation within blood cell lineages to favor erythropoiesis rather than Adipocytes also contain nonstructural metabolic precursors and energy for the purpose of lympho-hematopoiesis. This is a nonstructural function.
  • Adipocytes are essential for synthesizing plasma membranes during blood cell development because they contain cholesterol esters, triglycerides and lipoproteins.
  • Bone marrow and extramedullary adipocytes are critical for homeostatic control of temperature in the bone marrow microenvironment and throughout the body, and thus contribute to the overall energy metabolism of the organism.
  • Bone marrow adipose tissue is an essential endocrine organ.[4] Bone marrow adipose tissue (MAT) increases during caloric restriction (CR), is responsible for increased adipokine secretion, and alters skeletal muscle adaptation to These and other observations identify MAT as an endocrine organ.

BOTH Nonstructural and Structural Functions: In the following examples, adipose’s structural and nonstructural functions combine for the patient’s benefit:

  1. Reversal of damage caused by therapeutic radiation [60-63]
    • Structural (filling tissue defect) uses, and
    • Nonstructural tissue repair and regenerative uses [63]
  1. Treatingacute thermal injury [64-65]
    • Treating Pain Mitigating implant breast pain [66]
    • Improving post-mastectomy pain [67-68]
    • Improving lower back pain [70]
    • Nerveor neuroma repair [71-72]
  1. Healing ulcers
    • Treatingpressure sores [73]
    • Treating chronic non-healing anal fissures and associated stenosis [74]
  1. Treating vocal fold paralysis [75-77]
  2. Treating velopharyngeal insufficiency [78]
  3. Treating scleroderma and systemic sclerosis [79]
  4. TreatingDupuytren’s disease of the hand [80, 81]
  5. Treating Raynaud’s phenomenon – After fat grafting, there is improved symptomatology with evidence suggestive of measurably increased perfusion [82]
  6. Improving tendon repair
    1. Adipose tissue assists in tenolysis for foot and hand tendon [83]
    2. Treating adherent tendons and joints in burn patients with fat graft [84]
  7. Preventing osseous reunion of skull defects [85]
  8. Improvingthe quality of skin [86]

c.   Regulating an HCT/P’s risks based on the manufacturer’s intended use and mechanisms of action in the patient ensures meaningful evaluation and effective regulation of risk.

 The §§ 351-361 framework conditions the degree of regulatory oversight on the degree of an HCT/P’s risk. The homologous use and minimal manipulation criteria are central to determining whether an HCT/P will be classified as a § 361 or § 351 product, and if the latter, whether § 351’s “same surgical procedure” exception will apply. In turn, the existence of homologous use and minimal manipulation depend on the HCT/P’s structural or nonstructural function.  More specifically:

21 CFR 1271.3(c) defines homologous use as “the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.”

21 CFR 1271.3(f) evaluates minimal manipulation of structural tissue in terms of processing that does not alter “the original relevant characteristics of the tissue relating to” the tissue’s utility for reconstruction, repair, or replacement. For nonstructural tissues, it evaluates “the relevant biological characteristics of cells or tissues.”

Insisting that adipose be evaluated as exclusively structural precludes any evaluation of its nonstructural functions despite their presence and importance in the donor and intended use and therapeutic benefits for the recipient. Failing § 361’s homologous use and minimal manipulation criteria are virtually guaranteed. This effectively prohibits any nonstructural use, and precludes any meaningful evaluation of their risks.

As a result, it effectively prohibits patient access to safe nonstructural applications of adipose tissue and thereby undermines the FDA’s obligations to protect patients and promote innovation.

 The  “ same surgical procedure”  exception  to  §  351   also  becomes  completely  unavailable  for nonstructural use of adipose because it similarly requires homologous use and minimal manipulation.

◊ ◊ ◊ ◊ ◊ ◊ ◊

Recommendation #4: Revise the evaluation of minimal manipulation and homologous use as they pertain to particular applications of adipose tissue, (as detailed below).

 IFATS respectfully requests the FDA to reconsider three particular applications of adipose tissue with regard to homologous use and minimal manipulation, each of which is required for § 361 classification as well as § 351’s “same surgical procedure” exception. In specific, IFATS requests the FDA to change its prior examples of the absence of homologous use and/or minimal manipulation to recognize the following:

  • Decellularizing adipose tissue for structural use is minimal manipulation.
  • Structural use of fat in the breast constitutes homologous
  • Stromal vascular fractionation (SVF) of adipose to obtain nonstructural adipose components for use as a nonstructural tissue constitutes minimal

Each is explained in order
a.      Decellularizing adipose tissue for structural use is minimal manipulation.

 The draft guidance currently states that decellularizing structural adipose tissue constitutes more than minimal manipulation because the process alters the tissue’s ability to perform structural functions. This is incorrect. Adipose tissue’s structural functions are performed by a dense and interconnected skeleton of reticular fiber and dense connective tissue. Its biomechanical properties include tensile strength and elasticity, both of which are central to the structural functions of padding and cushioning.

Nonstructural components such as adipocytes, pre-adipocytes, lipids, etc. do not contribute to adipose’s  structural characteristics or functions. It is well recognized that decellularization leaves adipose’s structural components fully intact. It does not alter, disturb or weaken the remaining reticular fiber and dense connective tissue skeleton, or compromise its ability to perform structural functions. Multiple reports have demonstrated that decellularized adipose tissue retains structural properties and can be injected to impart padding and cushioning of soft tissues. [89-93]

The FDA already classifies decellularized dermis as minimally manipulated, thereby acknowledging that the process of decellularization does not alter structural characteristics or functions of the remaining structural matrix. Removing cells from dermis and removing cells from adipose employ comparable methods to achieve comparable results. Decellularizing adipose for structural use, like decellularizing dermis for structural use, does not alter structural characteristics.

For these reasons, IFATS respectfully requests the FDA to revise the draft guidance to recognize that decellularized adipose is minimally manipulated as required by § 361 and § 351’s “same surgical procedure exception.”

 
b.      Structural use of fat in the breast constitutes homologous use.

 Example B-3 of the draft adipose guidance states that application of adipose-based HCT/Ps to the breast is nonhomologous use because “[t]he basic function of breast tissue is to produce milk (lactation) after childbirth. Because this is not a basic function of adipose tissue, using HCT/Ps from adipose tissues for breast augmentation would generally be considered a non-homologous use.” This logic is flawed and must be corrected because it mischaracterizes the function of the breast, and mischaracterizes the function of adipose in breast surgery.

  • For the purpose of determining homologous use, the basic function of the breast is a secondary sex organ. In terms of shape, form and appearance, the breast is vital to a woman’s bodily integrity and body image, psychological sense of self, and overall physical and emotional health and well-being.
  • Lactation is not the sole or even primary function of the breast.
    • Most women never lactate, but their breasts do function as secondary sex organs throughout their adolescence and
    • When lactation does occur, it is episodic, time-limited, and accounts for a very small fraction of a woman’s lifespan.
    • Even when healthy, post-menopausal women cannot Restoring lactation is thus completely irrelevant to restoring breast function.
    • All men have breasts, thousands develop breast cancer each year, and many will need reconstructive surgery — even though men do not lactate.
  • Federal law recognizes and protects the breast’s importance as a secondary organ. 
    • The Women’s Health and Cancer Rights Act, 29 USC 1185b(a), requires group health insurers to cover “all stages” of breast reconstruction following mastectomy or irradiation, including bilateral correction of asymmetrical appearance where one breast is otherwise unaffected.
    • Restoring lactation is not a goal or even a remote concern of this In fact, lactation is never mentioned in the statute’s text, legislative history or associated regulations.
  • The function of adipose tissue in breast surgery is structural and therefore
    • Mastectomy removes more than the ability to lactate. It removes size, shape and form by removing the breast mound, which is predominantly adipose. Consequently, applying adipose tissue for the structural purpose of restoring form and shape is homologous use.
    • By classifying adipose based tissues as non-homologous when applied to the breast, an entire class of Centers for Medicare & Medicaid Services (CMS) approved breast reconstruction procedures would be at risk for not complying with the same surgical procedure For example:
  • Autologous free tissue flap transfer (“free flap” breast reconstruction) is performed by transferring complex musculocutaneous flaps containing adipose One of the most common methods of reconstruction, it qualifies as an HCT/P because it completely removes fat-containing tissue flaps from the body before implanting. [94-96] Fat grafting for breast reconstruction is another common clinical practice.
  • According to the draft adipose guidance, these and other methods of breast reconstruction could no longer be used without formal premarket approval because they do not restore lactation and are therefore non-homologous. Focusing solely on restoration of lactation ignores the fact that the breast is largely composed of fat tissue and its size, shape and form can be reconstructed with fat
  • This and other methods of breast reconstruction will no longer be available for clinical use under 361 or § 351’s same surgical procedure exception because they will not restore lactation.
  • Removing these and other reconstructive methods from clinical application has nothing to do with risk. It is instead a perverse outcome of insisting that breast reconstruction be evaluated for its ability to restore the breast’s minor and episodic function of lactation despite fat’s ability to restore the breast’s size, shape and function as a secondary sex organ.

For these reasons, IFATS respectfully requests the FDA to revise the draft HCT/P guidance documents to recognize that as applied to the breast, adipose tissue is homologous use because it performs the structural functions of restoring, repairing or reforming size, form and shape.


c.  When intended for a nonstructural use in the patient, stromal vascular fractio n (SVF)cells should be evaluated as nonstructural when determining minimal manipulated and homologous use.

 The FDA’s draft adipose guidance expressly acknowledges that adipose tissue contains a variety of nonstructural components, including adipocytes, preadipocytes, fibroblasts, vascular endothelial cells, a variety of immune cells, and also stores energy in the form of lipids. These are nonstructural because the cells perform the same regenerative functions in vivo as they do in vitro and animal models. [97- 98] Nonstructural adipose HCT/Ps are readily available in the stromal vascular fraction (SVF). Stromal vascular fractionation of lipoaspirate (typically obtained through liposuction) can remove fat’s structural components, making nonstructural SVF cells available for nonstructural use in a patient.  Just  as removing nonstructural cells through decellularization does not alter the relevant structural characteristics or structural function of the remaining structural matrix, removing structural components does not alter the relevant nonstructural characteristics or nonstructural function of the remaining nonstructural SVF components.

This is minimal manipulation under 21 CFR 1271.3(f)(2) because extracting nonstructural cells or tissues from lipoaspirate “does not alter the relevant biological characteristics of cells or tissues.”

Also, this is homologous use under 21 CFR 1271.3(c) because it uses lipoaspirate’s nonstructural HCT/Ps for “repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.”
Examples: Nonstructural adipose tissue for homologous use, with minimal and more than minimal manipulation à Reversal of radiation damage as intended nonstructural use

 Homologous use with no manipulation: Using liposuction aspirate to perform fat grafting/adipose tissue therapy for the intended use or of reversing radiation damage in the breast – a nonstructural function – is homologous use. The structural side-effect of increasing volume may be a collateral benefit, but the intended use is still nonstructural tissue repair.

  • Use is homologous because the HCT/P performs that same basic nonstructural function in both donor and

Homologous use with minimal manipulation: Using liposuction aspirate is indicated for the nonstructural function of reversing radiation damage in the neck without the volume gain of a fat graft.  Separating nonstructural from structural components obtains nonstructural SVF cells for nonstructural use in the patient.

  • Use is homologous because it is performing the intended nonstructural function of reversing radiation
  • Manipulation is minimal because processing does not alter relevant nonstructural biological characteristics.

Homologous use with more than minimal manipulation: Using liposuction aspirate is indicated for the nonstructural function of reversing radiation damage in the intestines by catheter injection of nonstructural SVF. However, an adequate dose is difficult to obtain because the patient is cachectic (low body fat caused by caloric depletion from radiation enteritis). Culture expansion is considered as a means of increasing dose.

  • Use is again homologous because SVF cells would perform the intended nonstructural function of reversing radiation
  • Manipulation is more than minimal because culture expansion of cells to yield a therapeutic dose alters relevant biological characteristic. SVF cells in their natural state do not engage in linear growth to create a homogeneous monoculture. Even tumors do not produce homogeneous monocultures.

Examples: SVF for nonhomologous use >>>Bone (re)generation

 SVF cells do not normally form bone in their native location. Delivering SVF cells to bone for the intended structural function of directly (re)generating new bone (via action of “stem cells”) might be considered. Processing might involve combining SVF cells with one or more additives (such as ex vivo culture media additives) for the intended structural function of (re)generating NEW bone (such as additives added to our culture medias ex vivo). For this scenario:

  • Use is nonhomologous because the basic function in donor and patient will differ if nonstructural SVF cells are combined with one or more additives (such as ex vivo culture media additives) for the intended structural function of (re)generating NEW bone (such as additives added to our culture medias ex vivo).
  • Manipulation is more than minimal because processing would alter the nonstructural SVF’s original relevant characteristics.

◊ ◊ ◊ ◊ ◊ ◊ ◊

The members of IFATS are grateful for the FDA’s willingness to re-open and extend the period for public comments and allow additional time for the September 2016 public hearing on the 2014-2015 draft HCT/P draft guidances. As a multidisciplinary scientific society composed of adipose stem cell biologists and clinician–scientists, IFATS would greatly appreciate the opportunity to work with the FDA in meeting the challenges of regulating HCT/P therapies. We respectfully request that representatives of the FDA, including the Director of CBER, meet with members of IFATS to discuss the issues addressed herein as well as others that pertain to the advancement and regulation of adipose-based therapies.

Respectfully submitted on behalf of IFATS,

Adam J. Katz, MD, FACS

Chair, IFATS Regulatory Affairs Committee & IFATS Co-Founder University of Florida College of Medicine

Professor

Director of Plastic Surgery Research,

Laboratory of BioInnovation and Translational Therapeutics Division of Plastic Surgery, Department of Surgery

 

IFATS BOARD OF DIRECTORS

 

Bruce Bunnell, PhD

Tulane University / United States

 

Louis Casteilla, PhD

University of Toulouse  / France

 

Sydney Coleman, MD

New York & Pittsburgh Universities / United States

 

Julie Fradette, PhD

Lavalle University / Canada

 

William Futrell, MD

Founders’ Board University of Pittsburgh / United States

 

Marco Helder, PhD

VU University Medical Center Amsterdam / The Netherlands

 

Adam J. Katz, MD, FACS

Founders’ Board University of Florida / United States

 

Ramon Llull, MD, PhD –

Founders’ Board University of Barcelona / Spain

 

Kacey Marra, PhD

University of Pittsburgh / United States

 

Ricardo Rodriguez, MD –

President (2016) Private Practice / Johns Hopkins / United States

 

Peter Rubin, MD, FACS – Chair, Founders’ Board Chairman of the Board

University of Pittsburgh / United States

 

Stuart K. Williams, PhD

University of Louisville / United States

 

MEMBERSAT-LARGE

 

Jeff Gimble, MD, PhD

Pennington Biomedical / United States

 

Keith March, MD, PhD

Indiana University / United States

 

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  2. Ter Horst E, Naaijkens B, Krijnen P, Van Der Laan A, Piek J, Niessen Induction of a monocyte/macrophage phenotype switch by mesenchymal stem cells might contribute to improved infarct healing postacute myocardial infarction. Minerva cardioangiologica. 2013;61:617-625
  3. Guisantes E,  Fontdevila  J,  Rodríguez    Autologous  fat   grafting   for   correction  of unaesthetic scars. Annals of plastic surgery. 2012;69:550-554
  4. Klinger M, Caviggioli F, Klinger FM, Giannasi S, Bandi V, Banzatti B, Forcellini D, Maione L, Catania B, Vinci Autologous fat graft in scar treatment. Journal of Craniofacial Surgery. 2013;24:1610-1615
  5. Klinger M, Marazzi M, Vigo D, Torre Fat injection for cases of severe burn outcomes: A new perspective of  scar  remodeling  and   reduction.   Aesthetic  plastic   surgery. 2008;32:465-469
  6. Khouri RK, Smit JM, Cardoso E, Pallua N, Lantieri L, Mathijssen IM, Khouri Jr RK, Rigotti Percutaneous aponeurotomy and lipofilling: A regenerative alternative to flap reconstruction? Plastic and reconstructive surgery. 2013;132:1280-1290
  7. Balkin DM, Samra S, Steinbacher Immediate fat grafting in primary cleft lip repair. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2014;67:1644-1650
  1. Rigotti G,  Marchi  A,  Galie  M,  Baroni  G,  Benati  D,  Krampera  M,  Pasini  A, Sbarbati.  Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: A healing process  mediated by  adipose-derived  adult  stem  cells.  Plastic  and  reconstructive surgery. 2007;119:1409-1422
  1. Villani F, Caviggioli F, Klinger F, Klinger Rehabilitation of irradiated head and neck tissues by autologous  fat   transplantation.   Plastic   and   reconstructive   surgery. 2009;124:2190-2191
  2. Chang CC,  Thanik  VD,  Lerman  OZ,  Saadeh  PB,  Warren  SM,  Coleman  SR,  Hazen   Treatment   of   radiation   skin   damage   with   coleman   fat   grafting.   STEM   CELLS. 2007;25:3280-3281
  3. Sultan SM, Stern CS, Allen Jr RJ, Thanik VD, Chang CC, Nguyen PD, Canizares O, Szpalski C, Saadeh PB, Warren Human fat grafting alleviates radiation skin damage in a murine model. Plastic and reconstructive surgery. 2011;128:363-372
  4. Loder S, Peterson JR, Agarwal S, Eboda O, Brownley C, DeLaRosa  S,  Ranganathan  K, Cederna P, Wang SC, Levi Wound healing after thermal injury is improved by fat and adipose-derived stem cell isografts. Journal of Burn Care & Research. 2015;36:70-76
  1. Sultan SM, Barr JS, Butala P, Davidson EH, Weinstein AL, Knobel D, Saadeh PB, Warren SM, Coleman SR, Hazen Fat grafting accelerates revascularisation and decreases fibrosis following thermal injury. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2012;65:219-227
  2. Cuomo R, Zerini I, Botteri G, Barberi L, Nisi G, D’ANIELLO Postsurgical pain related to breast implant: Reduction with lipofilling procedure. In Vivo. 2014;28:993-996
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  4. Caviggioli F,  Maione  L,  Forcellini D,  Klinger  F,  Klinger    Autologous  fat   graft   in postmastectomy pain syndrome. Plastic and reconstructive surgery. 2011;128:349-352
  5. Caviggioli F, Vinci V, Codolini Autologous fat grafting: An innovative solution for the treatment of post-mastectomy pain syndrome. Breast Cancer. 2013;20:281-282
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  7. Faroni A, Terenghi G, Reid Adipose-derived stem cells and nerve regeneration: Promises and pitfalls. Int Rev Neurobiol. 2013;108:121-136
  8. Vaienti L, Gazzola R, Villani F, Parodi Perineural fat grafting in the treatment of painful neuromas. Techniques in hand & upper extremity surgery. 2012;16:52-55
  9. Marangi GF, Pallara T, Cagli B, Schena E, Giurazza F, Faiella E, Zobel BB, Persichetti Treatment of  early-stage  pressure  ulcers  by  using  autologous  adipose  tissue  grafts. Plastic Surgery International. 2014;2014
  10. Lolli P, Malleo G, Rigotti Treatment of chronic anal fissures and associated stenosis by autologous adipose tissue transplant: A pilot study. Diseases of the Colon & Rectum. 2010;53:460-466
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REPROGRAMMED STEM CELLS

Scientists Confirm Reprogrammed Adult Stem Cells Identical to Embryonic Stem Cells

Click on photo (at left) to enlarge
Photo: iPS cells feature – reprogrammed stem cells: Credit: Moscow Institute of Physics and Technology

Russian researchers have concluded that reprogramming does not create differences between reprogrammed and embryonic stem cells.

Stem cells are specialized, undifferentiated cells that can divide and have the remarkable potential to develop into many different cell types in the body during early life and growth. They serve as a sort of internal repair system in many tissues, dividing essentially without limit to replenish other cells. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another more specialized cell type, such as a muscle cell, a red blood cell, or a brain cell. Scientists

distinguish several types of stem cells—pluripotent stem cells can potentially produce any cell in the body. No pluripotent stem cells exist in an adult body, rather they are found naturally in
early embryos.

There are two ways to harvest pluripotent stem cells. The first is to extract them from the excess embryos produced during invitro fertilization procedures, although this practice is still ethically and technically controversial because it does destroy an embryo that could have been implanted. For this reason, researchers came up with the second way to get pluripotent stem cells— reprogramming adult cells.

Reprogramming, the process of “turning on” genes that are active in a stem cell and “turning off” genes that are responsible for cell specialization was pioneered by Shinya Yamanaka, who showed that the introduction of four specific proteins essential during early embryonic development could be used to convert adult cells into pluripotent cells. Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon for the discovery that mature stem cells can be reprogrammed to become pluripotent.

reprogram3use

Production of iPS cells:
• Isolate cells from patient; grow in a dish •
Treat cells with “reprogramming”
• Wait a few weeks
• Pluripotent stem cells
• Change culture conditions to stimulate cells to differentiate into a variety of cell types
• blood cells  |   gut cells   |  cardio muscle cells
Credit: Moscow Institute of Physics and Technology

Thanks to their unique regenerative abilities, stem cells offer potential for treating any disease. For example, there have been cases of transplanting retinal pigment epithelium and spine cells from stem cells. Another experiment showed that stem cells were able to regenerate teeth in mice. Reprogramming holds great potential for new medical applications,  since reprogrammed pluripotent stem cells (or induced pluripotent stem cells) can be made from a patient’s own cells instead of using pluripotent cells from embryos.

However, the extent of the similarity between induced pluripotent stem cells and human embryonic stem cells remains unclear. Recent studies highlighted significant differences between these two types of stem cells, although only a limited number of cell lines of different origins were analyzed.

Researchers compared induced pluripotent stem cell (iPSC) lines reprogrammed from adult cell types that were previously differentiated from embryonic stem cells. All these cells were isogenic, meaning they all had the same gene set.

Scientists analyzed the transcriptome – the set of all products encoded, synthesized and used in a cell. Moreover, they elicited methylated DNA areas, because methylation plays a critical role in cell specialization. Comprehensive studies of changes in the gene activity regulation mechanism showed similarities between reprogrammed and embryonic stem cells. In addition, researchers produced a list of the activity of 275 key genes that can present reprogramming results.

Researchers studied three types of adult cells – fibroblasts, retinal pigment epithelium and neural cells, all of which consist of the same gene set; but a chemical modification (e.g. methylation) combined with other changes determines which part of DNA will be used for product synthesis.

Scientists concluded that the type of adult cells that were reprogrammed and the process of reprogramming did not leave any marks. Differences between cells that did occur were thought to be the result of random factors.

“We defined the best induced pluripotent stem cells line concept,” says Dmitry Ischenko, MIPT Ph.D. and Institute of Physical Chemical Medicine researcher.

The minimum number of iPSC clones that would be enough for at least one to be similar to embryonic pluripotent cells with 95 percent confidence is five.”

programmed stem cellsClearly, no one is going to convert embryonic stem cells into neurons and reprogram them into induced stem cells. Such a process would be too time-consuming and expensive. This experiment simulated the reprogramming of a patient’s adult cells into induced pluripotent stem cells for further medical use, and even though the reprogramming paper, published in the journal Cell Cycle, does not currently propose a method of organ growth in vitro, it is an important step in the right direction. Both induced pluripotent cells and embryonic stem cells can help researchers understand how specialized cells develop from pluripotent cells. In the future, they may also provide an unlimited supply of replacement cells and tissues that can benefit many patients with diseases that are currently untreatable.

The study, titled, “An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion,” concluded that reprogramming does not create differences between reprogrammed and embryonic stem cells, involved researchers from the Vavilov Institute of General Genetics, Research Institute of Physical Chemical Medicine, and the Moscow Institute of Physics and Technology (MIPT).

###

human stem cells

Breakthrough in scaling up life-changing stem cell production

Scientists from the U.K. and Sweden have discovered a new method of creating human stem cells that could solve the problem of meeting large-scale production needs, allowing researchers to fully realize the potential of stem cells for understanding and treating disease.

Human pluripotent stem cells are undifferentiated cells that have the unique potential to develop into all the different types of
cells in the body. With applications in disease modeling, drug screening, regenerative medicine and tissue engineering, there is already an enormous demand for these cells, and that demand will continue grow as their use in clinical settings and the pharmaceutical industry increases.

Human embryonic stem cell line HUES1 grown in the new conditions E8+Inter-alpha-inhibitor and imaged for stem cell marker Oct4 (green) and cell-cell attachment molecule E-cadherin (red) with nuclear counter-staining (blue). Credit: Dr. Sara Pijuan-Galito and Dr. Cathy Merry, Wolfson Centre for Stem Cells, Tissue Engineering & Modelling and Centre for Biomolecular Sciences, The University of Nottingham Read more at: http://phys.org/news/2016-07-breakthrough-scaling-life-changing-stem-cell_line

Human embryonic stem cell line HUES1 grown in the new conditions E8+Inter-alpha-inhibitor and imaged for stem cell marker Oct4 (green) and cell-cell attachment molecule E-cadherin (red) with nuclear counter-staining (blue).
Credit: Dr. Sara Pijuan-Galito and Dr. Cathy Merry, Wolfson Centre for Stem Cells, Tissue Engineering & Modelling and Centre for Biomolecular Sciences, The University of Nottingham
Read more at: http://phys.org/news/2016-07-breakthrough-scaling-life-changing-stem-cell.html#jCp

However, production of stem cells at the scale required for optimal application in modern research and healthcare has not beenfeasible because available culture methods are either too expensive, or reliant on substances that would not be safe for clinical use in humans.

The research results, published in Nature Communications in July, describe how the scientific team from The University of Nottingham’s Wolfson Centre for Stem Cells, Tissue Engineering and Modelling at Uppsala University in Sweden and GE Healthcare also in Sweden have identified and improved human stem cell culture methods that could lead to quicker and cheaper large scale industrial production of human pluripotent stem cells.

By using a protein derived from human blood called Inter-alpha inhibitor, the team has grown human pluripotent stem cells in a minimal medium without the need for costly and time-consuming biological substrates. Inter-alpha inhibitor is found in human blood at high concentrations, and is currently a by-product of standard drug purification schemes.

The human serum-derived protein can make stem cells attach to unmodified tissue culture plastic, eliminating the need for coating in defined human pluripotent stem cell culture, and improving survival capabilities of the stem cells in harsh conditions.

It is the first stem cell culture method that does not require a pre-treated biological substrate for attachment, and therefore, is more cost and time efficient, paving the way for easier and cheaper large-scale production.

Existing methods are time consuming and make developing human stem cell cultures prohibitively costly. This new method has the potential to save time and money in large-scale and high-throughput cultures, and be highly valuable for both basic research and commercial applications.

The work began at Uppsala University, and the study’s first author, Sara Pijuan-Galitó PhD., is continuing her work as a Swedish Research Council Research Fellow at Nottingham.

Researchers now intend to combine Inter-alpha inhibitor protein with an innovative hydrogel technology to improve on current methods for controlling cell differentiation, and also apply it to disease modelling. The discovery, according to the findings, will help facilitate research into many diseases although their focus is currently on understanding rare conditions like Multiple Osteochondroma) at the cellular level. The aim is to replicate the 3 dimensional environment that cells experience within the body so that lab-bench biology is more accurate in modelling diseases.

human stem cells linePijuan-Galitó has been awarded the Sir Henry Wellcome Postdoctoral Fellowship at Nottingham University for her work on the research, which will enable her to combine Inter-alpha inhibitor with improved synthetic polymers in collaboration with fellow regenerative medicine pioneers Professor Morgan Alexander and Professor Chris Denning. The team plans to further improve on current human stem cell culture by designing an economical and safe method that can be easily translated to large-scale production and can deliver billions of stem cells necessary move cellular therapeutics forward in patient settings.

The study, titled “Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture,” was published in Nature Communications in July, 2016.

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liver stem cell research

Purest Liver-like Cells to Date Generated from Induced Pluripotent Stem Cells (iPSCs)

Researchers from the Medical University of South Carolina (MUSC) and the University of Pennsylvania have discovered a new methodology for purifying liver cells generated from induced pluripotent stem cells (iPSCs) that could facilitate progress toward an important clinical goal: treating patients with disease-causing liver mutations by transplanting unmutated liver cells derived from their own stem cells.

This new technique follows previous attempts to generate liver-like cells from stem cells, which have yielded heterogeneous cell populations with little similarity to diseased livers in patients.

liver cell

Image: induced pluripotent stem cells expressing a characteristic cell surface protein called SSEA4 (green).
Credit: Image courtesy of Stephen A. Duncan, Ph.D., at the Medical University of South Carolina

The National Heart, Lung, and Blood Institute (NHLBI)’s Next Generation Genetic Association Studies Program (Next Gen) was created to bank stem cell lines sourced from patients in genome-wide association studies (GWAS). The goal of the Next Gen Lipid Conditions sub-section – a collaborative effort between Stephen A. Duncan, Ph.D., chair of regenerative medicine at MUSC and Daniel J. Rader, M.D. and Edward E. Morrisey, Ph.D., both at the University of Pennsylvania – is to help determine the genetic sources of heart, lung or blood conditions that also include the liver.

The GWAS studies map the genomes in hundreds of people as a way to look for genetic mutation patterns that differ from the genomes of healthy individuals. As GWAS study map more genomes, they become more likely to find the correct genetic mutations that cause a disease. Once a panel of suspected mutations is built, stem cells from these individuals can be manipulated in culture dishes to differentiate into any of the body’s cells. The cells can be screened to learn more about the mutations and to test panels of drugs that might ultimately help treat patients harboring a disease.

Problems arise during the cell manipulation process. For example, iPSCs persistently refuse to mature uniformly into liver-like cells when fed growth factors. Traditionally, antibodies have been used to recognize features of maturity on the surfaces of cells and purify cells that are similar, an approach that has been crucial to stem cell research. But available antibodies that recognize mature liver cells are scanty and tend to recognize many different kinds of cells. The many types of cells in mixed populations have diverse characteristics that can obscure underlying disease-causing genetic variations, which tend to be subtle.

“Without having a pure population of liver cells, it was incredibly difficult to pick up these relatively subtle differences caused by the mutations, but these differences are important in the life of an individual,” Duncan says.

Instead of relying on antibodies, Duncan and his team embraced a new technology called chemo proteomic cell surface capture (CSC) technology. CSC technology allowed the researchers to map the most highly produced proteins on the surface of liver cells during the final stages of differentiation of stem cells into liver cells. The most abundant protein was targeted with an antibody labeled with a fluorescent marker and used to sort the mature liver cells from the rest.

The procedure was highly successful: The team had a population of highly pure, homogeneous and mature liver-like cells. Labeled cells had far more similar traits of mature hepatocytes than unlabeled cells. Pluripotent stem cells that had not differentiated were excluded from the group of labeled cells.

“That’s important,” says Duncan. “If you’re wanting to transplant cells into somebody that has liver disease, you really don’t want to be transplanting pluripotent cells because pluripotent cells form tumors called teratocarcinomas.”

closed system kit N-BiotekDuncan cautioned that transplantation of iPSC-derived liver cells is not yet ready for translation to the clinic, but the technology for sorting homogeneous liver cells can be used now to successfully and accurately model and study disease in the cell culture dish.

“We think that the ability to generate pure populations will get rid of the variability, and therefore really help us combine with GWAS studies to identify allelic variations that are causative of a disease, at least in the liver,” he says.

Researchers at the University of Minnesota (Minneapolis) and the Medical College of Wisconsin (Milwaukee) contributed to the study, published August 25, in Stem Cell Reports.

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