Stem cell therapy for peripheral nerve injury: illustrative cases

Abstract

BACKGROUND

Stem cell therapy is undergoing rapid evolution, as evidenced by preclinical studies showcasing the successful promotion of peripheral nerve regeneration using various stem cell types. Despite the absence of clinical studies that demonstrate both efficacy and safety, there has been a notable increase in the number of commercial entities marketing and promoting stem cell therapies for peripheral nerve injury (PNI) directly to patients.

OBSERVATIONS

The authors present the cases of 5 patients who sustained traumatic PNIs and received stem cell therapy via various routes of delivery (including intramuscular, perineural, intrathecal, and intravenous administration) prior to presenting to the authors for evaluation. No objective functional improvement was noted in any of these patients at long-term follow-up.

LESSONS

High-quality studies and greater involvement of academic surgeons on social media platforms are essential in today’s landscape to promote education, provide leadership, and foster meaningful engagement, ultimately ensuring the best possible treatment outcomes for patients regarding the role of stem cell therapies in PNIs.

https://thejns.org/doi/10.3171/CASE24878

Stem cell therapy is a promising treatment option for various medical conditions, representing a significant focus in current medical research. Although only approved by the US FDA for the treatment of certain hematological disorders, stem cell therapy has been purported to improve the treatment of various other conditions, including heart disease,¹ peripheral vascular disease,² spinal cord injuries,³ traumatic brachial plexus,^4–6 and peripheral nerve injuries (PNIs).⁷

The trend of global medical tourism for patients to undergo unregulated stem cell therapies has emerged as a growing concern. Despite a few exceptions, such as hematopoietic progenitor cell transplantation for leukemia, which is generally acknowledged as a proven and safe procedure, many other forms of stem cell therapy lack sufficient regulation and evidence of efficacy, thus posing significant risks to patients and their economic well-being.⁸ While stem cell medical tourism is a highly controversial practice, news media portrayals in the patients’ countries, e.g., Canada, the US, the United Kingdom, Australia, and New Zealand, between 2006 and 2009 advertised overly optimistic and unrealistic benefits, risks, and efficacy.⁹ Despite recent increased media and policy scrutiny, stem cell medical tourism providers have not become discouraged and, in fact, continue to promote and advocate for stem cell transplants on their websites.¹⁰,¹¹

Stem cell therapy for PNI remains in the experimental stage. A systematic review in 2021¹² showed 5 different types of mesenchymal stem cells that have been reported in peripheral nerve regeneration: bone marrow stem cells with 19 articles, adipose-derived stem cells (ADSCs) with 18 articles, umbilical cord–derived mesenchymal stem cells/amniotic fluid mesenchymal stem cells with 11 articles, dental pulp stem cells with 7 articles, and skeletal muscle stem cells with 3 articles. Of the 45 publications, only 1 case was in humans. A radial and median nerve gap reconstruction using sural nerve autograft and a collagen neurotube with skin-derived stem cells around the coaptation site was reported. The 3-year follow-up showed functional recovery of the patient.⁷

Since our initial report,¹³ we have encountered 5 additional patients who underwent stem cell treatments before presenting to our multidisciplinary peripheral nerve clinic. This cohort included 3 patients with brachial plexus injuries and 2 with PNIs. In this report, we discuss social media implications on stem cell treatments and the role of academic surgeons in this type of injury and treatment.

Illustrative Cases

Case 1

A 78-year-old man presented with a sciatic nerve injury after a right total hip replacement. Immediately after surgery, he developed a right foot drop. Postoperative electrodiagnostic (EDX) studies confirmed a sciatic nerve injury. He underwent stem cell treatment and different types of electrical stimulation treatments. Two years later, he presented to our clinic. The patient found no sustained improvement from the stem cell and stimulation treatments. Muscles innervated by the tibial nerve were weak for tendon transfer, and muscles innervated by the peroneal nerve did not present any reinnervation. Only the biceps femoris muscle demonstrated minimal recovery. A decompression of the peroneal nerve at the fibular head was performed. The poor success rate of this operation, considering the time between injury and surgery, was discussed in detail with the patient.

Case 2

A 31-year-old man asked for a virtual consultation with our team. He had a documented history of depression and anxiety. Five years before, he had a sciatic nerve neuropathy proximal to the popliteal fossa with compartment syndrome and rhabdomyolysis in his right leg following a drug overdose incident. He was seen by an acupuncturist who recommended that he undergo porcine stem cell injections into his medial calf. He underwent these injections and had significant side effects. He experienced increased weakness and changes in sensation. The exact content of the injectant was not known to the patient, and it was not obtainable when the patient asked for it. Later, he was evaluated in an external peripheral nerve unit, where a conduction block of the peroneal nerve at the fibular head was identified and surgically decompressed. The patient had some degree of improvement after this surgery, with less pain. Although the patient sought consultation from our peripheral nerve unit, he ultimately did not present to our institution for further assessment or treatment.

Case 3

A 62-year-old man presented to our clinic with weakness in his right arm following a C2–T1 laminectomy and fusion. He had a 10-year history of cervical stenosis and underwent the surgery 18 months prior. Immediately after the procedure, the patient experienced bilateral flaccidity in his upper extremities, which persisted in the right arm. The left arm recovered rapidly. He did not report any sensory disturbances. A similar episode had occurred previously after an L4–S1 fusion when he developed lower extremity paresthesias and chronic left foot drop. EDX studies confirmed bilateral brachial plexopathy. Over the past 18 months, he underwent intensive physical therapy and stem cell therapy, including injections into the brachial plexus area performed in Peru, followed by systemic administration of what the patient believes were ADSCs. He reported initial improvement in his lower extremity paresthesias, but these symptoms have since returned to their previous state. On physical examination, the patient demonstrated limited shoulder movement (30° of abduction and flexion), elbow flexion graded at Medical Research Council (MRC) grade 2, and good hand function. We proposed continued physical therapy with a myoelectric orthosis to enhance elbow flexion.

Case 4

A 32-year-old man presented to our clinic with a left lower trunk plexus injury resulting from a motor vehicle accident 2.5 years earlier. His injuries also included a scapular fracture, multiple rib fractures, and thoracic spine fractures (T2–4). He underwent brachial plexus exploration, neurolysis, and a transfer of the C7 nerve root to C8 in California. Subsequently, the patient received fetal stem cell therapy in Ukraine, administered subcutaneously and intravenously. He reported almost complete resolution of left upper extremity pain 4 weeks after the injections, with long-standing pain relief but no motor function improvement. EDX studies revealed severe brachial plexopathy involving muscles innervated by the lower and middle trunks. On physical examination, the patient exhibited flickers of activity in finger extensor muscles and no activity in finger flexor muscles. The sensation was absent in the long, ring, and small fingers. Subtle Horner’s syndrome was noted on the left side. Tendon transfer surgery to improve hand function was discussed with the patient.

Case 5

A 40-year-old man presented to our clinic with right upper extremity weakness, a sequela of West Nile virus infection 10 months prior. His symptoms initially began with headache and back pain, followed 8 days later by flu-like symptoms and a sudden onset of right upper extremity weakness. Over the past few months, he reported some improvement in elbow flexion but no progress in shoulder movement. He underwent stem cell therapy at a local facility via intravenous administration, which did not result in functional improvement. He had also been using electrical stimulation. EDX studies revealed no activation in the shoulder. On physical examination, the patient demonstrated no active shoulder motion, MRC grade 3 strength in the biceps, MRC grade 1 in the brachioradialis, MRC grade 2 in the triceps, and MRC grade 4 in wrist and finger flexors and extensors. The sensation was intact. Physical therapy was recommended, and shoulder fusion was discussed as a potential future option.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

In recent years, we have observed an increased use of stem cell therapies, likely driven by the rise in advertising from commercial agents and the influence of social media. Building on our previously published cases¹³ of 3 patients with traumatic brachial plexus injuries, the additional 5 cases provide further insight into the broader patterns and outcomes of unregulated stem cell therapies. Consistent with the earlier cases, none of the new patients demonstrated meaningful functional recovery attributable to these treatments. The first 3 cases primarily involved periplexal and intrathecal injections, and the outcomes showed no significant clinical improvement. In the 5 cases presented in this report, administration methods varied more widely, including intravenous, intramuscular, and subcutaneous routes. Regardless of the delivery method, functional outcomes remained poor, and a lack of formal documentation or standardization of treatment protocols was observed in all 8 patients.

The application of stem cells for PNI entails several considerations. First, in any PNI, there are 3 different scenarios: the nerves could be compressed, stretched but in continuity, or ruptured. For the first 2 types of injuries, spontaneous recovery is possible. After a nerve rupture, the continuity of the nerve should be reestablished by direct coaptation or with interposition nerve grafts. The use of autografts to reestablish a nerve gap remains the standard of care after a PNI.^14,15 To validate the use of stem cells in human PNI, cases of clean nerve ruptures treated with stem cells need to be compared with an autograft control group. Drawing definitive conclusions from studies of this nature would prove challenging due to the diverse array of factors influencing nerve regeneration, including but not limited to age, size of the nerve gap, and the specific type and location of the nerve involved.

Autologous nerve grafts contain Schwann cells that support axonal regeneration in addition to a conduit to guide axonal growth. The ability to use cells without harvesting grafts would be a benefit. This is where stem cell therapy plays a role. The underlying principle is that transplanted stem cells differentiate into the needed cell types and promote nerve regeneration by functioning as support cells with their powerful paracrine effects, releasing growth factors that promote nerve regeneration.¹³,¹⁶ The route of delivery is important. Three of our patients had stem cell injections intravenously (cases 3–5), one into the nerve (case 3), one into the muscle (case 2), and one subcutaneously (case 4). The location of the stem cell injection for case 1 was not documented. Intramuscular bone marrow–derived mononuclear cell injections could potentially increase myofiber diameters and motor unit amplitudes in chronic partially denervated muscle⁴ but are unlikely to restore voluntary tibialis anterior muscle control in a proximal sciatic nerve injury such, as seen in our case 1. Similarly, for cases 3–5, based on our current physiological understanding, it is challenging to assert that injecting stem cells into the bloodstream aids in the axonal growth of damaged nerves. Intraneural application of stem cells, such as in case 3, using a needle and penetrating the epi-perineurium, poses a risk of causing axonal damage. Additionally, the infiltration of stem cells can lead to increased pressure within the nerve, potentially producing a higher intraneural pressure and ischemia.

Stem Cell Medical Tourism, Social Media Implications, and the Role of Academic Surgeons

The administration of stem cells lacking adequate testing, production without good manufacturing practice standards, and no clinical oversight present significant risks. A comprehensive review conducted in 2018 identified 35 instances of acute and chronic complications, including fatalities (n = 9), associated with stem cell interventions performed for unverified indications across 14 countries.¹⁷ Among these cases, 6 involved intraspinal injections of olfactory cells for spinal cord injuries, resulting in complications such as meningitis (n = 3), fever (n = 2), and the development of neoplastic growth originating from an intramedullary olfactory epithelium mass (n = 1). The proliferation of businesses engaged in direct-to-consumer marketing of stem cell interventions is alarming. A study conducted in 2016 identified 351 such businesses operating at 570 clinics in the US.¹⁸ The magnitude of this industry has escalated significantly, with the number of businesses soaring to 1480, spanning 2754 clinics as of March 2021.¹⁹ Stem cell medical tourism has also emerged as a substantial sector, with more than 400 websites advertising stem cell–based interventions for a wide spectrum of medical conditions²⁰ The estimated cost per stem cell treatment in 2014 ranged between $10,000 and $60,000 (USD), exclusive of travel expenses.²¹

A comprehensive examination of 68 stem cell clinic websites revealed that 90% purported the safety of treatment, while 15% misleadingly claimed that there was “no risk” involved.²² In recent years, social networks such as YouTube, X (formerly Twitter), and Facebook have emerged as important sources of health information for the general public and have also been utilized as a form of viral marketing, spreading messages quickly through the online community.²³ A study by Kamenova et al.¹¹ showed that the tone of most tweets (60.2%) on the social media platform X (formerly Twitter) was overwhelmingly positive, and there were rarely critical discussions about significant health risks associated with unproven stem cell therapies.

Lessons

Social media use is growing inexorably, and there is public demand for accurate medical information. If academic surgeons and researchers are not involved in social media, individuals with less knowledge of the field (in pursuit of commercial objectives) will take advantage of this powerful tool.²⁴ Today’s academic surgeons should advance the values that form the core of surgical practice: inclusion, leadership, innovation, scholarship, and mentorship.²⁵ Collaboration has the power to improve patient care.

We recognize the limitations inherent in retrospective studies, which rely on patient-reported histories. These accounts can be influenced by recall inaccuracies, particularly regarding the specifics of the stem cell treatments, such as cell type, dosage, and administration techniques. Additionally, the lack of standardized documentation (if any) from the treatment providers further complicates the ability to assess or compare the interventions objectively. Regardless of the specific data on stem cells, there is currently no scientific evidence to support the use of these therapies in the PNIs discussed in this article.

In conclusion, 5 cases of traumatic nerve injuries that received stem cell therapy by different routes of delivery (intramuscular, perineural, and intravenously) were presented. None of the patients benefited from such treatment. Social media platforms are utilized to promote and attract patients for these unproven treatments. We advocate for increased involvement of academic surgeons on social media platforms for purposes of education, leadership, and engagement.

Disclosures

Dr. Shin reported consulting for TriMed Orthopedics, royalties from Mayo Medical Ventures/TriMed Orthopedics, and being the editor in chief of Techniques in Hand & Upper Extremity Surgery outside the submitted work.

Author Contributions

Conception and design: Spinner, Shin. Acquisition of data: Spinner, Maldonado, Lee. Analysis and interpretation of data: Spinner, Maldonado, Shin. Drafting the article: Spinner, Maldonado. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Spinner. Study supervision: Shin.

Correspondence

Robert J. Spinner: Mayo Clinic, Rochester, MN. spinner.robert@mayo.edu.