Regenerative Medicine in the Foot and Ankle

Regenerative medicine, also known as stem cell therapy, promotes the repair response of diseased or injured tissue using stem cells or their derivatives. The therapy has advanced to encompass wound care, orthopedic and podiatric injuries, autoimmune disease, inflammation, neurological conditions, cancer, amyotrophic lateral sclerosis (ALS), lupus, stroke recovery, and much more.
What is exciting about stem cell therapy is its nature to divide and change into whatever cell type is needed to assist in repairing damaged tissue. Regenerative medicine in podiatry has a wide variety of applications including, but not limited to wound care, tendonitis, scar tissue, cartilage damage, fusions, and nerve damage.

Much of the focus for regenerative medicine in podiatry is in the form of mesenchymal stem cells (MSCs). These are adult stem cells not derived from embryonic tissue. MSCs can be easily harvested from bone marrow, which can be done intraoperatively. One can take advantage of the known benefits of using such an autograft. One of the most critical aspects of MSC is the property of cells maturing into new types of cells, or differentiation.¹

MSCs are also self-replicating, which is important, because if stem cells were used to treat a tendon injury, the cells will not only differentiate into tendon cells, but will replicate exponentially to increase the effectiveness of the therapy.¹ The differentiation of MSCs into specific mature cell types is controlled by various cytokines, growth factors, extracellular matrix molecules, and transcription factors.² Transcription factors have been shown to directly regulate the progression to maturation of stem cells. The effect may occur by upregulating the expression of genes responsible for induction and progression of specific cell type differentiation. MSCs are able to migrate and seed specifically into damaged tissue sites, where they can differentiate into functional cells to replace damaged or diseased cells.³ The main properties of MSCs are anti-inflammatory, antibacterial, neurogenetic, apoptotic, synaptogenetic, angiogenetic.

Defensins are host defensive antimicrobial peptides that are active against bacteria, fungi, and viruses. Neurotrophins are growth factors that induce survival development and function of neurons. This is especially important with patients with diabetic neuropathy—not necessarily to cure their neuropathy, but to restore existing nerve function with tissue injury. These growth factors are proteins that bind to cell receptors and regulate cellular processes and promote cell growth.  They can be cell specific or nonspecific.²  

A Closer Look at PRP in the Lower Extremity

The most common form of regenerative medicine using mesenchymal stem cells is platelet-rich plasma (PRP), which is harvested from blood and put through a centrifuge to separate the platelet rich plasma from the red blood cells and platelet poor plasma. There has been great debate and a plethora of studies about the efficacy of PRP.

PRP is a biological product defined as a portion of the plasma fraction of autologous blood with a platelet concentration above the baseline.⁴ Platelets contain an abundance of growth factors and cytokines that can affect inflammation, angiogenesis, stem cell migration, and cell proliferation. Harvest sites have been shown to matter with regard to the quality of PRP. When compared to whole blood, direct bone marrow harvest demonstrates a higher concentration of growth factors and cytokines.

Several Level I and Level II randomized controlled studies have demonstrated that PRP injections in plantar fasciitis patients have overall better pain scores and decrease in thickness of tendons over patients that were injected with corticosteroids.^5,6 There is plenty of literature supporting PRP’s use in plantar fasciitis but evidence is lacking in Achilles tendinopathy. In a 2017 study by Chimenti et al the authors concluded that PRP for these conditions remains controversial.⁷ Two Level V retrospective case series for insertional Achilles tendinopathy pathology show just 53% and 57% patient satisfaction.^8,9

In my practice, I have used PRP injections with Achilles tendonitis, plantar fasciitis and tendon tears in the capacity of an isolated procedure and as an adjunct to more involved repairs with good results. Most studies suggest that PRP has a higher efficacy when used earlier in the treatment protocol. It may be difficult to have patients pay out-of-pocket early on in the treatment cycle due to a lack of insurance coverage. Most patients seem to opt for PRP as a last resort prior to surgery.  

What You Should Know About Exosomes

A newer derivative of mesenchymal stem cells are exosomes, which are extracellular vesicles isolated from MSCs. They essentially function as MSCs and act to reduce inflammation and facilitate paracrine signaling capable of strengthening the body’s defenses and advancing its healing processes. Studies have indicated that bone marrow–derived MSC derived extracellular vesicles can downregulate inflammation and upregulate tissue repair in humans. Extracellular vesicles are about 30–150 nm in size and are involved in direct cell-to-cell communication. The purification process results in a concentration of proteins, messenger RNA (mRNA) and growth factors, without any of the original cell’s DNA. The lack of DNA makes rejection of these cells impossible, lowering the risk of exosomes’ use.¹⁰

A 2019 study studied the effect of exosomes from tendon stem cells (TSCs) on tendon injury healing.10 A rat Achilles tendon tendinopathy model was established by collagenase-I injection. This was followed by intra-Achilles tendon injection with TSCs or exosomes. The authors concluded exosomes from TSCs could be an ideal therapeutic strategy in tendon injury healing for its balancing tendon extracellular matrix and promoting the tenogenesis of TSCs.¹⁰ This is indicated mostly in the form of an injectable. It would be used in a similar way to amnion or PRP injections.  

Exploring the Potential of Amniotic Stem Cells

Another derivative of mesenchymal stem cells that is widely used in podiatry is amniotic stem cells. Most commonly used for tendon repair, wound care, nerve tissue repair, and scar tissue prevention, amniotic stem cells are made of mesenchymal stem cells. Amniotic stem cells contain collagen types III, IV, V, and VII and fibronectin and laminin mesenchymal cells, and also contain fibroblasts, growth factors, and hyaluronic acid.¹¹

Human amniotic membrane has 2 primary components: amnion and chorion.¹² Amnion consists of organized collagen-rich extracellular matrix, viable cells, regulatory proteins, and signaling molecules. It has 5 distinct layers: the epithelium, basement membrane, compact layer, fibroblast layer, and spongy layer. Chorion is 3 to 4 times thicker than amnion, and has a reticular layer, basement membrane, and trophoblast layer. Amniotic membrane grafts have numerous developmental cytokines, which play important roles in tissue formation.^11,12  

In wound healing, amniotic membranes use the aforementioned properties to help support wound healing. Most importantly, I have found they use the essential growth factors to convert chronic wounds stuck in the inflammatory phase into the acute phase of healing.

I currently use amniotic membranes both intraoperatively and in the office, most commonly for tendon repair and wound care. I am able to apply the membranes for wound care in the office weekly with noticeable results. There are limitations such as infection, heavily fibrotic or highly exudative wounds.

There are good studies that involve injection of amnion into tendon tissue. Werber and colleagues studied a total of 44 patients experiencing chronic plantar fasciosis and Achilles tendinosis, with a mean age of 55 and 47.7 years, respectively, who were all unresponsive to multiple standard therapies for a minimum of 6 months, were treated with one implantation of amnion fluid around the plantar fascia and or Achilles tendonitis.¹¹ There was significant improvement in the visual analogue score (VAS) pain scores in all patients, from a pre-injection average pain score of 8.2 to a post-injection week 4 average score of 5.2. By postoperative week 10 the pain scores on average were 1–3 on a visual analog scale. All patients in this study experienced heel or Achilles pain, unresponsive to standard therapy protocols. After treatment, all patients noted significant pain reduction, indicating that granulized amniotic membrane and amniotic fluid can be successfully used to treat both chronic plantar fasciosis and Achilles tendinosis.

Insights on ESWT and EPAT

Noninvasive treatments of regenerative medicine include extracorporeal pulse activation technology (EPAT), a form of extracorporeal shockwave therapy (ESWT). Acoustic waves with high energy peak interact with tissue causing the effects of accelerated tissue repair, cell growth, analgesia, and mobility restoration. Typically, patients do 3–5 shockwave treatments every 5–7 days.

There are quite a few recent studies supporting ESWT in Achilles tendinopathy. In a 2019 study by Stania and colleagues, the data of 66 patients with chronic Achilles tendinopathy (CAT) received ESWT was reviewed.¹³ According to the disease courses, those cases were allocated to short-term group (symptom duration 3–6 months) and long-term group (symptom duration 6 months). The authors concluded ESWT could effectively relieve pain and improve function of hindfoot in patients with chronic Achilles tendinopathy, and ESWT could specifically offer better benefits to functional improvement in patients with short durations of CAT symptoms.

Another Level 1 randomized controlled trial examined the effectiveness of an eccentric loading program followed by stretching exercises combined with ESWT or sham ESWT for treating chronic noninsertional Achilles tendinopathy in both the short and long term.¹⁴ Twenty-two men and 28 women aged 18 to 40 years were allocated into 2 equally matched groups. Function and pain were assessed at baseline, 1 month, and 16 months. The authors concluded that combining calf eccentric loading with stretching exercises resulted in significant improvements in the pain and functional scores in patients with noninsertional Achilles tendinopathy. Adding ESWT to this combined protocol resulted in significantly greater improvements in both the short and long term. This treatment modality is widely used in our profession.

EPAT is typically an out-of-pocket cost to the patient; however, there is good data to suggest high patient satisfaction.¹⁴ Affordable equipment and low learning curve for the provider, make this a viable option for all podiatrists.

Using MLS Lasers in the Foot and Ankle

Another noninvasive regenerative medicine technique is multi-wave lock (MLS) laser. This modality, approved by the Food and Drug Administration, is a newer robotic laser technology that decreases inflammation, swelling and pain through a series of laser treatment. MLS technology delivers therapeutic wavelengths, 808nm (anti-edemic and anti-inflammatory) and 905nm (analgesic).

The difference between MLS laser therapy and low-level laser therapy is MLS is able to induce strong anti-inflammatory, anti-edema, and analgesic effects simultaneously and within a short period of time. Low-level laser therapy cannot achieve these results because of the limitations of using 1 or 2 wavelengths that are not synchronized.

Most conditions have protocols that range from 6–10 treatments. The treatments are cumulative and are delivered 2–3 times per week for 2–3 weeks. This is a great option for patients who want to avoid any sort of invasive treatment. Insurance coverage, out-of-pocket costs and compliance are limiting factors for success.

A 2017 study aimed to evaluate the efficacy of a high-power, dual-wavelength near-infrared laser source in the treatment of patients affected by tendinopathies.¹⁵ At the end of the treatment, each subgroup showed an improvement in pain symptoms; considering all the patients, a 56.9% reduction in the mean VAS score was observed after laser treatment. The authors suggest that MLS therapy can be effectively applied for pain control and function improvement in patients affected by tendinopathies.

A 2013 study evaluated 45 patients between ages 42 and 55 with chronic Achilles tendinopathy using triple laser therapy.¹⁶ MLS laser triple therapy uses 808nm and 1064nm wavelengths, whereas MLS uses 808nm and 905nm, so they are similar. They concluded triple laser therapy promoted the tissue trophism and the reduction of inflammatory response in a shorter time, if compared with other treatments, reducing the operating costs and the need for more complex interventions. Additional studies can help achieve better patient outcomes and hopefully coverage of these noninvasive regenerative treatments.  

Pertinent Insights on Ultrasound-Guided Modalities

Ultrasound-guided percutaneous tenotomy/fasciotomy is ultrasonic energy utilized to emulsify and remove tissue by a working tip that oscillates at high frequencies.

An 18-gauge stainless steel inner tube is connected to a series of piezoelectric crystals that are electronically driven at high frequencies to produce low amplitude oscillations. Pressurized lavage fluid emerges between the outer plastic tube and the stainless steel inner tube, cooling the working tip and providing fluid for lavage and debris removal. This essentially removes the pathologic tissue causing pain, which facilitates healing. A retrospective review evaluated 26 procedures in 25 patients.¹⁷ These procedures included treatment for plantar fasciitis, Achilles tendinitis and posterior tibial tendinitis. The mean Foot Function Index scores were as follows: pain, 8.53%; disability, 7.91%; activity limitation, 2.50%; and overall, 6.97%. Twenty index procedures were successful, and two patients repeated the procedure successfully for an overall 84.6% success rate with mean surveillance of 16 months.

There were no infections or systemic complications.¹⁷ This is a more invasive treatment modality that involves incisions, albeit minimally invasive. This can be used more easily for larger chronic tendonitis/tendinosis. More commonly in the Achilles tendon, plantar fascia, posterior tibial tendon, and peroneal tendons. This is a great option for those who have failed PRP or amnion injections, but it lacks the indication for an open repair.

In Conclusion

Regenerative medicine is an important clinician tool to have. The group of patients that do not want any surgical treatment or want to do physical therapy seem to fit the criteria. These patients have usually had pain for 3–6 months and failed other treatments. However, we may want to switch to these treatments earlier. The 2019 study that examined chronic Achilles tendinopathy did show greater improvement in patients with shorter term symptoms.3 Physicians may hesitate because of the out-of-pocket costs associated with these treatments but if patients can get back to activity faster it is worth exploring earlier.  

A great deal of research is still needed to assess current treatment and future progress for regenerative medicine. It can be the key to prolonging a healthy human life. Once of the main limiting factors to the proliferation of regenerative medicine is access to treatment. A current lack of insurance coverage may make most of these treatments cost prohibitive. Once more adequate studies are published, there will be more accessibility for these treatments, and the development of more proven novel techniques for healing.

Dr. Parthasarathy is in private practice in Silver Spring, Md. She currently serves on the Board of Directors of the American Board of Podiatric Medicine (ABPM) and is Chair of the American Podiatric Medical Association (APMA) Communications Committee and member of the APMA Education Committee. She serves on the Editorial Board of Advisors of Podiatry Today. She is also Treasurer on the Maryland Podiatric Medical Association’s Executive Committee. Dr. Parthasarathy was previously a Podiatry Section Chief at the Medstar Montgomery Medical Center in Olney, Md., and is a past recipient of the APMA Rising Star Award (2017). 

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