Regenerative Treatment at AZCCPP

Introduction

Perinatal allograft products, such as those derived from amniotic membranes, umbilical cord, and placental tissues, have been used in regenerative medicine for over a century. The first documented use of amniotic membrane allografts was in 1910 for skin grafting, where they outperformed xenografts (tissue obtained from animals) and cadaveric grafts (tissue obtained from cadavers). These products gained further recognition in the mid-20th century when researchers discovered their immune-privileged properties, effectively minimizing rejection.

In recent decades, the application of placental-derived tissues has expanded substantially, particularly in wound healing, orthopedics, and soft tissue repair, owing to their regenerative and anti-inflammatory characteristics.

What is pudendal neuralgia?

Pudendal neuralgia, which is characterized by pain in the pudendal innervation area, can be triggered by various factors. Common causes include nerve compression due to spasming pelvic floor muscles, tight ligaments, scar tissue, or nerve inflammation without compression. Unfortunately, diagnostic tests are unable to differentiate between these mechanisms. Consequently, at AZCCPP, we use a stepwise approach to diagnosis and treatment. Initially, we address pelvic muscle spasms. If pelvic muscle spasms are identified during the examination, we recommend vaginal or rectal suppositories containing muscle relaxants, refer patients for pelvic floor physical therapy, and administer injections of botulinum toxin (Botox, Daxxify). If the muscles have relaxed but the pain persists, we then proceed to treat the pudendal nerves. The initial treatment involves injecting human placental mesenchymal stem cell exosomes (hpMSC-Exo), which we offer to all patients suspected of having nerve injury. If these treatments fail to provide relief, we turn to surgical decompression of the pudendal nerve (pudendal neurolysis) as a last resort.

What are human placental mesenchymal stem cell exosomes (hpMSC-Exo)?

Exosomes are tiny particles (30–150 nanometers in size) released by cells into their surroundings, carrying important materials such as proteins, RNA, and lipids. Human placental mesenchymal stem cell exosomes (hpMSC-Exo) are extracted from placental tissue. The cells from which they are derived are characterized by their ability to differentiate into various cell types, including those that form connective tissues such as bone, cartilage, muscle, and fat, as well as nerve tissue such as neurons and Schwann cells.

Exosomes obtained from mesenchymal placental cells contain bioactive molecules, such as growth and anti-inflammatory factors, that can influence other cells. Thus, they are a promising tool in regenerative medicine. Exosomes have shown remarkable potential in nerve healing, and studies suggest that injecting them can significantly reduce pain levels and enhance functionality in various pain conditions.

Two of the exosomes' most crucial actions are nerve regeneration and protection. They achieve this by stimulating the growth of nerve cells and Schwann cells. Schwann cells produce myelin, a protective coating that insulates nerve fibers and acts as an insulator to the nerve. These cells are essential for nerve repair. Additionally, exosomes promote axonal regeneration, which involves the growth of axons, a part of nerve cells (neurons) responsible for transmitting electrical impulses.

The second, equally vital aspect of exosomes is their remarkable ability to modulate the anti-inflammatory response. Inflammation is not just a temporary nuisance; it often follows nerve injury and significantly hinders the healing process. By effectively reducing this inflammation, exosomes create the optimal environment necessary for robust nerve regeneration. Emphasizing the crucial role of exosomes in managing inflammation underscores their potential to revolutionize recovery outcomes in nerve injuries.

Additionally, placental exosomes play a vital role in promoting the growth of blood vessels within the injured region, thereby enhancing the healing process and mitigating inflammation.

What are the differences between stem cells and stem cell-derived exosomes?

Stem cells and exosomes are distinct biological entities with unique properties, roles, and therapeutic applications.

Stem cells are living, undifferentiated cells with the remarkable ability to self-renew and differentiate into specialized cell types. They play a crucial role in tissue regeneration and growth by replacing damaged cells. When injected into the body, stem cells can replicate indefinitely, maintaining their population. They have the potential to differentiate into various cell types, including muscles, nerves, and blood vessels. Although there is no risk of malignant transformation of placental stem cells, it has been shown that some stem cells may trigger an immune response.

Exosomes, on the other hand, are small vesicles found within the cell. They are approximately 1/100 the size of the cell, resembling a tiny soap bubble. Exosomes contain numerous growth and anti-inflammatory factors. Unlike stem cells, which are living cells, exosomes cannot replicate, eliminating the risk of malignant transformation. Moreover, they do not provoke an immune response from the body.

Exosomes have a big advantage because they contain more therapeutic products than stem cells. A regular vial of stem cells has about 25 to 30 million cells, while a vial of exosomes has 15-75+ billion exosomes. This means exosomes are about 1000 times more concentrated, making them a stronger and safer treatment option.

How are human placental mesenchymal stem cell exosomes obtained?

Placental mesenchymal stem cells (MSCs) are obtained from bioethically donated birth tissue provided by healthy, consenting mothers who have undergone comprehensive medical background checks and blood screenings. These mothers have delivered their babies through full-term, live cesarean section births. Importantly, none of the products used in our office are derived from abortion or pregnancy termination.

The extraction of MSCs entails a series of meticulous steps, including tissue decontamination and dissection. Following this, exosomes are isolated from these stem cells through multi-step filtration and other techniques. Although these processes are costly and time-consuming, they produce a high-purity exosome product.

Who are the patients who benefit from (hpMSC-Exo) injection?

Patients suffering from pudendal neuralgia or pudendal pain, who have successfully treated pelvic floor muscle spasms but still experience pain, may benefit from hpMSC-Exo injections. These injections can help reduce inflammation and support nerve regeneration. This treatment is most effective when there is no nerve compression; however, there isn’t a reliable test to confirm or rule out this compression. Therefore, we recommend hpMSC-Exo injections for all patients who still have pudendal neuralgia after effectively treating muscle spasms. If hpMSC-Exo treatment does not work, the patient might be considered for pudendal nerve decompression surgery.

What products do we use in our practice?

At AZCCPP, we exclusively use products from a life sciences company accredited by the American Association of Tissue Banks (AATB) and registered with the Food and Drug Administration (FDA).

The procurement of fetal placenta, umbilical cord, and amniotic membranes occurs solely within the United States and complies with AATB guidelines. The main priority is the health and safety of both the mother and the baby, ensuring their well-being is valued above the procurement process.

Every batch undergoes rigorous testing, which accounts for 20% of the total product. These tests cover a wide range of sterility checks, including the detection of all fungi, molds, yeasts, and bacteria, as well as endotoxins, multiple viruses, and various other diseases.

The products are delivered directly from the producer to AZCCPP in a frozen state and are promptly stored in our freezer until they are ready for injection. Typically, two products—from the placental tissue and umbilical cord tissue—are combined to provide a complete set of growth and anti-inflammatory factors. They are thawed immediately before the injection and loaded into a syringe.

 

Are treatments with hpMSC-Exo FDA-approved?

Though not yet fully approved by the FDA for regenerative medicine, these products, also known as Human Cell and Tissue Products (HCT/Ps), are regulated by the FDA’s Center for Biologics Evaluation and Research (CBER). Numerous well-designed scientific studies have demonstrated their safety and efficacy as allografts; however, the FDA has yet to review these claims.

The laboratory supplying AZCCPP with regenerative medicine products is registered with the FDA (U.S. Food and Drug Administration) and accredited by the AATB (American Association of Tissue Banks).

What other conditions can be treated by placental exosomes?

Currently, clinical Phase I trials are underway to evaluate the therapeutic potential of human mesenchymal stem cell exosomes (hpMSC-Exo) in the treatment of premature ovarian failure. hpMSC-Exo has also been investigated for its potential in treating chronic obstructive pulmonary disease (COPD), osteoarthritis, traumatic brain injury, Crohn’s disease, COVID-19-associated acute respiratory distress syndrome, and Alzheimer’s disease. Furthermore, there are suggestions that placental exosomes may be utilized in wound healing, bone and cartilage regeneration, the treatment of neurological conditions such as Parkinson’s disease and autoimmune conditions, and as a delivery vehicle for anti-cancer agents.

In many of these cases, placental exosomes are administered intravenously. For nerve injuries, they are injected directly around the nerve or into the surrounding tissue.

What are the side effects of treatment with these regenerative medicine products?

Human cell and tissue products (HCT/Ps) are generally considered safe with minimal side effects. Some patients may experience temporary headaches, nausea, fatigue, or loss of appetite. There is no evidence to suggest that the risk of adverse, immunologic, or oncologic reactions is elevated in patients who receive these allografts. Numerous well-designed scientific studies have demonstrated the safety and efficacy of these allografts; however, the FDA has not yet evaluated these claims.

How are the hpMSC-Exo injected?

The hpMSC-Exo can be injected near nerves, into inflamed areas, or through intravenous routes for systemic effects. At AZCCPP, we do not perform intravenous infusions of these products; these are usually done by regenerative medicine providers.

In our practice, we administer hpMSC-Exo around nerves, particularly the pudendal nerve or its branches, or directly into tissues. We often use a combination of two HCT/Ps, including an umbilical cord product that resembles platelet-rich plasma and provides healing and regenerative benefits. This second product contains various collagens and hyaluronic acid, along with other proteins, lipids, and nucleic acids, enhancing the localized effectiveness of exosomes. Additionally, hyaluronic acid is known for its ability to reduce adhesion formation.

The need for sedation is dictated by the injection site. Depending on the specific muscle or nerve targeted, ultrasound guidance may also be required.

It remains unclear whether these HCT/Ps can be mixed with a local anesthetic, so at AZCCPP, we avoid using nerve blocks with local anesthetics when administering them.

Can hpMSC-Exo be done at the time of botulinum toxin injection?

At AZCCPP, we refrain from administering HCT/Ps simultaneously with botulinum toxin products (Botox, Daxxify) during pelvic floor muscle injections. The primary reason for this practice is that we always perform pudendal nerve blocks when administering botulinum toxin. If these procedures were performed together, the local anesthetic and HCT/Ps would be delivered to the same area. Although it remains unclear whether local anesthetics could adversely affect the allograft or reduce its effectiveness, we prioritize caution and avoid conducting both procedures at the same time.

How to prepare for the procedure?

HCT/Ps injections are performed in our office, and the choice of whether to administer sedation depends on the injection site. Please refrain from using aspirin products for five days before the injection. However, other nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Motrin), naproxen, and acetaminophen (Tylenol) are acceptable and do not require discontinuation. Patients taking blood thinners must stop those medications. If you are on blood thinners, please consult your hematologist regarding how to discontinue them before your procedure.

For patients scheduled for the procedure under sedation, please avoid eating or drinking anything for eight hours beforehand. Additionally, we kindly request that all patients use an enema prior to the procedure. Purchase two Fleet enemas from any pharmacy. Approximately half an hour before leaving your house or hotel, while seated on the toilet, remove the cap from the enema bottle and insert it into your rectum. Squeeze out the entire contents of the enema and repeat the process with the second bottle. You should be able to evacuate almost immediately.

Now, you’re all set to come to the office.

The procedure

Please arrive at the office no later than 15 minutes before the scheduled procedure. Patients undergoing their procedure under anesthesia must have an adult accompany them. Please let our office know if you can’t have anyone accompany you. We can facilitate hiring a nursing agency to provide you with transportation home and immediate post-procedure care.

Your procedure will take place in our Scottsdale office. If you are scheduled to receive sedation for the procedure, you will meet with an anesthesiologist and a nurse who will be present during the process. They will conduct a brief interview with you, and afterward, you will be directed to the changing room, where you will need to undress from the waist down and cover yourself with a paper gown. A nurse or anesthesiologist will then start an IV, and EKG leads will be placed on your chest. Next, you will position yourself in stirrups; if necessary, an examination will be conducted to identify the areas of pain. Some procedures do not require a prior exam. After that, you will receive sedation, and the allografts will be injected. Generally, you will wake up about 10 minutes after the procedure and be taken to the recovery area before discharge. If necessary, pain medications will be sent to your pharmacy. Complications and emergencies following the regenerative medicine treatment are exceedingly rare, but if you have any urgent questions, please call the office at (480) 599-9682. For non-urgent questions, please use the portal to contact our office. Questions submitted through the portal will be answered on Mondays and Fridays, and all inquiries received before noon MST will be addressed on those days. 

What should you expect during and after the injections of hpMSC-Exo?

After the procedure, there may be a temporary increase in pain and symptoms caused by nerve and muscle irritation. This irritation should subside within a week following the injection. Patients who received the injection vaginally might experience some vaginal spotting for 1 to 2 days afterward. Those with pelvic floor muscle spasms may notice increased spasms after the injection, making it more challenging to empty the bladder or bowels. This typically resolves within 12 hours after the injection.

What are the outcomes of injections of regenerative medicine treatments in pudendal neuralgia?

For skin rejuvenation, noticeable results usually appear within 6 to 8 weeks after treatment and can last an average of 6 to 8 months. However, some patients may experience effects that last as long as two years. In nerve healing studies, the effects may take several months to become noticeable. Based on our preliminary observations at AZCCPP, over 50% of patients benefit from these regenerative treatments.

In plain English

Human cell and tissue products (HCT/Ps) come from the placenta of a full-term cesarean section. Scientists remove small sacs called exosomes or extracellular vesicles (EVs) from those placental stem cells. These exosomes contain substances that promote healing and reduce inflammation. Healing factors help repair tissue, while anti-inflammatory substances minimize swelling at the injection site. Less inflammation leads to less pain and faster recovery. These benefits usually appear within a few weeks after the injection.

At AZCCPP, we give injections using two products: one from the placental bundle/umbilical cord tissue, and another from the umbilical cord itself. These products work together to provide growth factors, anti-inflammatory agents, and proteins that make the treatment more effective. The injections can be administered near nerves or directly into muscles and surrounding tissues. Depending on where the injection is given, some patients may require sedation.

After receiving an injection, some people might feel increased pain or worsening symptoms. Because of this, the doctor may prescribe pain medication to help during the initial recovery period. About half of patients report feeling better after receiving regenerative medicine treatments. Due to very strong anti-inflammatory properties, some individuals notice improvements within a few weeks, while others may see results after 6 to 9 months as their tissues heal.

Glossary

Allograft – is the transplantation of cells, tissues, or organs from one individual to another within the same species, but not between genetically identical individuals. A perinatal allograft is a type of tissue transplant derived from perinatal tissues, such as the placenta, umbilical cord, and amniotic fluid, which are collected after childbirth (typically during cesarean sections) with the donor’s consent.

Botulinum toxin – is a neurotoxic protein produced by the bacterium Clostridium botulinum. It works by blocking nerve signals that cause muscle contractions, leading to temporary muscle paralysis. This property makes it useful for treatment of muscle spasticity. Two types of botulinum toxin used in our practice are Botox and Daxxify.

EV’s – extracellular vesicles – exosomes

Exosomes are tiny, bubble-like structures (30–150 nanometers in size) released by cells that act as messengers, carrying proteins, genetic material (such as RNA), and other healing signals to help repair and regenerate damaged tissues. They originate from various cells, particularly mesenchymal stem cells (MSCs) like those found in the placenta, and provide a “cell-free” therapy option.

HCT/P’s – human cell and tissue products. Biological products are obtained from human cells and tissues. One such product is human placental mesenchymal stem cell exosome extract.

hpMSC-Exo – human placental mesenchymal stem cell exosomes – microscopic vesicles located in the human placental stem cell filled with growth factors and anti-inflammatory factors. They are considered human cell and tissue products.

Mesenchymal stem cells (MSCs) – are special adult stem cells that can develop into different types of cells, such as bone, cartilage, fat, and muscle cells. They are found in tissues like bone marrow, fat, placenta, and umbilical cord tissue. MSCs are widely used in regenerative medicine because they can repair damaged tissues, reduce inflammation, and support healing by releasing helpful molecules and signals to other cells

Placenta – is a temporary organ that develops in the uterus during pregnancy. It connects the fetus to the uterine wall and provides oxygen, nutrients, and hormones to support fetal growth. The placenta also removes waste products through the umbilical cord.

Pudendal nerve entrapment – compression of the pudendal nerve by ligaments, scar tissue, or surgical material (mesh, sutures),

Pudendal neuralgia – pain in the area of innervation of the pudendal nerve

Regenerative medicine products – are therapies designed to repair, replace, or regenerate human cells, tissues, or organs to restore normal function. These products leverage the body’s natural healing processes or utilize engineered solutions to address damage caused by age, disease, trauma, or congenital conditions. In this handout, we use the terms HCT/P’s, hpMSC-Exo, EV’s, allograft, and regenerative medicine products interchangeably.

Stem cells – are unspecialized cells in the body that have the unique ability to divide and self-renew, as well as develop into different types of specialized cells.

Umbilical cord - The umbilical cord is a flexible, tube-like structure that connects a developing fetus to the placenta.

Pudendal nerve pseudo-entrapment – compression of the pudendal nerve by spasming pelvic floor muscles