Revolutionizing orofacial pain management: the promising potential of stem cell therapy

Abstract

Orofacial pain remains a significant health issue in the United States. Pain originating from the orofacial region can be composed of a complex array of unique target tissue that contributes to the varying success of pain management. Long-term use of analgesic drugs includes adverse effects such as physical dependence, gastrointestinal bleeding, and incomplete efficacy. The use of mesenchymal stem cells for their pain relieving properties has garnered increased attention. In addition to the preclinical and clinical results showing stem cell analgesia in non-orofacial pain, studies have also shown promising results for orofacial pain treatment. Here we discuss the outcomes of mesenchymal stem cell treatment for pain and compare the properties of stem cells from different tissues of origin. We also discuss the mechanism underlying these analgesic/anti-nociceptive properties, including the role of immune cells and the endogenous opioid system. Lastly, advancements in the methods and procedures to treat patients experiencing orofacial pain with mesenchymal stem cells are also discussed.

Keywords: MSC secretome; mechanisms of stem cell anti-nociception; orofacial pain; stem cell analgesia; trigeminal pain.

Figure 1

Common tissue sources of stem cells.

Figure 2

Proposed immune interactions of MSCs with host immune cells that lead to anti-inflammatory phenotype, the release of endogenous opioids, and pain relief.

Figure 3

Classical description and pain map of neuropathic pain, then causing a secondary temporomandibular disorder. *neuropathic pain is “constant” and “burning”. *Neuropathic pain has a poor response to opioid drugs such as codeine. *Development of secondary TMD in the masseter, temporalis, occipital and supraspinal muscle groups.

Figure 4

Image of the lipoaspirate after mechanical emulsion and centrifugation. Upper layers of yellow adipose fat and free lipid. Middle liquid phase layer of saline, plasma, local anesthetic, red cells. Lower layers of ADSCs (pinkish white) and small dark red cell layer at the very bottom.

Figure 5

ADSCs freshly acquired from the stromal vascular fraction (SVF). ADSCs show excellent development and activation. Centrally located red cell in the image shows size comparison of the cells. Image taken at 1000X magnification with an oil immersion objective.

Figure 6

Samples of flow cytometer assays from patients undergoing stem cell therapy for orofacial pain. A small aliquot of ADSCs are used for quality control assessment of the adipose tissue processing. Assays conducted with a MUSE Cell Analyser (Merck Millipore Ltd.) and performed for annexin V (apopotosis), autophagy (cell breakdown), H2A.X (DNA damage) and tumorgenicity marker Pi3. (A) assays are baseline measurements taken 10 min after stem cell administration, (B) ADSCs subsequently exposed to high dose gamma radiation for several days to simulate stem cell deterioration and changes to the cell profiles that occurs with aging, certain disease states and medical radiotherapy.

Figure 7

Confirmation of proliferative aspects of ADSCs. Macrosopic upper image taken at 4 days after ADSCs plated in wells with 8 ml hydrogel. Left well shows cell proliferation throughout the gel matrix and right well used as control gel. Higher resolution lower image at 50X shows multiple colony forming units (CFUs) indicating excellent stem cell proliferative characteristics.

Figure 8

Ultrasound of right temporomandibular joint of healthy subject showing normal architecture of mandibular condyle (MC), mandibular fossa (MF), superior joint space (SJS) and the three sections of the meniscus (anterior, intermediate and posterior).

Figure 9

Peptidic chemotactic alginate-based hydrogel. Drop of blood placed in central well with perforations in the central well to allow cell migration into the surrounding peptide hydrogel. Image taken at 4 days incubation at 37C and show excellent hematopoeitc stem cells (HDSCs) migration and proliferation.

Figure 10

A 45 year old male with facial neuropathic pain and sympathetically maintained pain. There was six year pain history of right maxillary and mandibular trigeminal neuralgia. Previous treatments included seven neurosurgical operations (microvascular decompression, pulsed radiofrequency, nerve ablation), multiple Botox and ketamine/lidocaine infusions, high dose carbamazepine and gabapentin. Baseline thermograms before stem cells showed sympathetically maintained pain in the right maxilla with surface temperature differential −1.2C on the painful right maxilla (33.3C) compared to the left non-painful maxilla (34.5C) (normal range +/- 0.2C). Thermograms repeated at five weeks after stem cell injections showed nil surface temperature differential (bilateral 31.8C) showing resolution of neurovascular pain.