PEMF and diabetic foot ulcers

The published clinical trials for use of PEMF to treat diabetic foot ulcers are somewhat promising but not really there to prove a mechanism of action. WikiMedia Commons images of diabetic foot ulcers are featured at the top of this post to give impression that this is a horrifying condition. Wikipedia authors have created an extensive page on diabetic foot ulcers. Neuropathy is one factor. A patient is more likely to injure a foot if they cannot feel it. Decreased perfusion seems obvious based on the images. Decreased nitric oxide production seems to be a good root cause of the decreased perfusion. This post takes the stance that PEMF will never be a stand alone therapy for something a complicated as diabetic foot ulcers. Sadly the published clinical trials are not that great. This post will mention an ongoing PEMF/red light therapy clinical trial and a pre-clinical endeavor that could possibly benefit from PEMF.

Table: Published PEMF Clinical trials for diabetic foot issues

Reference	condition	company	# subjects	field	frequency	time	Outcome
Tassone 2023	distal neuropathy	Regenesis Biomedical Inc., Scottsdale, Arizona	182		27.12 MHz		⇓ pain and and improved skin perfusion pressure.
Kwan 2015	foot ulcer	Model XKC-600W; Magnetopulse International, Morley, Western Australia	13	12G	12 Hz	14 1hr in 3 wk	18% ⇓ wound size
Pieni 2008	foot ulcer	Therapeutic Magnetic Resonance (TMR®) a matress of sorts	40	40-60 μT	pulse packet 2.89-25.9 Hz. pulse trains 0.3-2.8 Hz,	14 days	more frequent and faster healing of DFUs
Weintraub 2009	foot pain	y Nu-Magnetics, Inc	225	6 0.18T static magnets	rotate 500 to 1500 rev/min.	2hr day 3 mo	no reduction neuropathic pain.
	foot ulcer		26	120 Hz	0.4-0.9 mT	2hr/day, 2x week, forearm	no difference in the healing time.

Piomics Medical

Piomics Medical is currently recruiting for a clinical trial combining red light therapy and PEMF. See Clinicaltrials.gov. Read about the COMS^® mechanism of action. Note that this device is extremely low frequency PEMF. These are some exerts from the clinical trial description.

The COMS One device incorporates technologies for optical and magnetic stimulation. The optical stimulation component is designed to emit light by two types of light emitting diodes (LEDs) in the wavelength of 660 nm (red) and 830 nm (near infrared) range of the electromagnetic spectra. The magnetic stimulation component is generated by a coil emitting pulse modulated magnetic fields in the extremely low frequency (ELF) range of the electromagnetic spectra. The System is a lightweight, portable device. The device is applied via a single use disposable component (COMStouch) that provides a base and sterile barrier for the unit. The device is attached via a single use strap (COMSfix). The device has been slightly adapted in order to make sure blinding is achieved/maintained. The specific feature that has been modified for the purposes of blinding is sensor detecting whether the device is lying on the skin.

The study designers didn’t say how long and often the session was to be applied. They are monitoring outcome measures every 12 weeks. Other than that, patients receive standards of care. This trial is going to be so important for practitioners of similar devices. The primary outcome measure is total wound closure 12 weeks after treatment. The secondary outcome measures are also worth following.

Outcome Measure	Measure Description	Time Frame
Median time to 50% wound area reduction	Time in number of days until wound area is reduced by 50% compared to wound area at time of randomization	24 weeks
Median time to 90% wound area reduction	Time in number of days until wound area is reduced by 90% compared to wound area at time of randomization	24 weeks
Incidence of complete wound closure	Incidence of complete wound closure after 8, 16, 20, and 24 weeks, which is defined as complete skin re-epithelialization without drainage	8 week, 16 week, 20 week and 24 week
Partial wound closure	Percent Wound Area Reduction (PWAR) at week 8, 12, 16, 20, 24	8 week, 12 week, 16 week, 20 week and 24 week
Incidence of all related or serious adverse events	Number of subjects with one or more related adverse event or serious adverse events Related adverse events are those judged by the investigator to be possibly, probably, or definitely related to the COMS One device or other trial procedures.	24 weeks
Time to target diabetic foot ulcer re-occurrence	Time in number of days from randomization until re-occurrence of the target diabetic foot ulcer, assessed up to 24 weeks	Up to 24 weeks
Time to amputation	Time in number of days from randomization until amputation associated with the target diabetic foot ulcer, assessed up to 24 weeks	Up to 24 weeks
Pain assessment	Wong-Baker FACES Pain Rating Scale – patient chooses the face that best demonstrates the physical pain they are experiencing at four time points throughout study participation	Week 1, Week 8, Week 12, Week 24
Quality of life survey	36-Item Short Form Survey (SF-36) – health-related quality of life questionnaire that is completed by patients at four time points throughout study participation	Week 1, Week 8, Week 12, Week 24

The other exciting thing about this trial is that it has clinics in the United States as well.

Ceria nanoparticles and micro RNA[1,2], can PEMF help?

January 20, 2024 – Ceria Therapeutics, Inc. (Ceria), an Arizona-based biotech startup focusing on the development of novel therapeutics to address several inflammatory diseases, announced that the company has received a fourth Small Business Innovation Research (SBIR) grant from the National Institutes of Health (NIH) directed to the development of CTX-001 for the treatment of non-healing diabetic foot ulcers (DFU).These are ceria nanoparticles with microRNA for the purpose of promoting angiogenesis in diabetic foot ulcers. Micro RNA are short, single stranded RNA that bind to messenger RNA in such a way as to decrease their ability to be translated into proteins. Ceria Therapeutics has identified key players in angiogenesis that are positively and/or negatively regulated by miRNA.

Figure 1 Mechanisms of angiogenesis affected by microRNAs.

Endothelial cells line blood vessel walls and are the main cells affected by processes of angiogenesis.

• Circulating pro-angiogenic growth factors like vascular endothelial growth factor (VEGF) , basic fibroblast growth factor, and epidermal growth factor are promoted by Mir20b-5p and negatively regulated by many more micro RNA. See the 15/20 Hz section stimulates blood vessel growth via VEGF in the Schumann Resonance post.
• Intracellular signaling second messengers include the extracellular signal-regulated kinases-mitogen activated protein kinases (ERK-MAPK) and phosphatidylinositol 3-kinase (PI3K)-Protein Kinase B (AKT) pathways, See the related post on this site.
• Intracellular protein Sprouty (Spry) inhibits ERK-MAPK signaling to down regulate angiogenesis. Additionally, mouse wounds treated with a topical gel formulation containing Spry2 exhibited impaired angiogenesis with inhibited endothelial cell migration and decreased MAPK signaling. There are micro RNAs to inhibit Spry2,

Zwitterion hydrogels for nanoparticle delivery [2]

The authors demonstrated a fabrication method for photopolymerized zwitterionic hydrogels that also enables sustained drug delivery over time of cerium oxide nanoparticle tagged with microRNA. The hydrogels exhibit a wide range of stiffness and mechanical properties depending on their monomer content. [2] Wikipedia authors have assembled the usual very technical accounts of hydrogels. No mention of the zwitterion variety.

Liu 2022 have a good cartoon of zwitterion hydrogels used for antifouling.

Note the presence of positive and negative functional groups in these gels. The positively charged groups can be on the surface with a negatively charged group between the surface of the “strings” that make up the polymer. The exact composition of the Ceria zwitterion hydrogels is not public access. OubMed has five publications on combining PEMF and hydrogels.

Hydrogels and PEMF

If say a practitioner were to think that PEMF would enhance the action of a hydrogel applied to wounds, here is a quick table of peer reviewed studies.

Publication	hydrogel	drug	system	PEMF
Zhang 2019	tetra-PEG/agar hydrogel + Fe3O4	diclofenac sodium	soft tissue injury	static, 0.3T
Wang 2020	gelatin Fe3O4	Celecoxib	tendon	pulsed magnetic therapy apparatus, 301-M9,
Li 2022	β-cyclodextran/gelatin, alginate	dopamine modified	cartilage	Physio Signal, 10T/s, 15 Hz, Orthofix Medical Inc, USA
Yucong 2022	cross-linked Na alginate	dopamine modified	bone marrow stem cell	burst 15 Hz, pulse 3.85 kHz, slew rate of 10 T/s.
Sakhrani, 2023	collagen	none	cell culture cartilage	75 Hz, 0.2 T

Summary

Published PEMF clinical trials for diabetic foot ulcers are interesting but probably not dramatic. Piomics Inc has got a very interesting clinical trial going on in the United States that could be transferrable to other very low frequency EMF/ infra and red light technologies. Ceria Therapeutics has a micro RNA based technology for diabetic foot ulcers. There is a very large overlap in potential mechanism of action with PEMF. PEMF has even been used with hydrogels to potentiate the release of the drug.

References

1. Lyttle BD, Vaughn AE, Bardill JR, Apte A, Gallagher LT, Zgheib C, Liechty KW. Effects of microRNAs on angiogenesis in diabetic wounds. Front Med (Lausanne). 2023 Mar 20;10:1140979. PMC free article
2. Stager MA, Bardill J, Raichart A, Osmond M, Niemiec S, Zgheib C, Seal S, Liechty KW, Krebs MD. Photopolymerized Zwitterionic Hydrogels with a Sustained Delivery of Cerium Oxide Nanoparticle-miR146a Conjugate Accelerate Diabetic Wound Healing. ACS Appl Bio Mater. 2022 Mar 21;5(3):1092-1103.
3. Lyttle BD, Vaughn AE, Bardill JR, Apte A, Gallagher LT, Zgheib C, Liechty KW. Effects of microRNAs on angiogenesis in diabetic wounds. Front Med (Lausanne). 2023 Mar 20;10:1140979. PMC free paper