Name: Prospective, Randomized, and Controlled Study of a Human Umbilical Cord Mesenchymal Stem Cell Injection for Treating Diabetic Foot Ulcers (Video) | JoVE Journal
Uploaded: 2023-03-03T13:55:00.000+00:00
Duration: 4 min 9 s
Description: Learn a standardized protocol for treating diabetic foot ulcers using human umbilical cord mesenchymal stem cell injections. This randomized controlled study evaluates safety, effectiveness, and wound healing outcomes.

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5 minutes

The authors thank the Affiliated Hospital of Xuzhou Medical University for its cooperation, including the recruitment and follow-up of patients with diabetic foot wounds. The authors also thank the patients who participated in the patient needs survey during the design of this study.
The author(s) announce the receipt of the following financial support for research, authorship, and/or publication of this article: National Natural Science Foundation of China 82172224, Postgraduate Research &#38; Practice Innovation Program of Jiangsu Province (SJCX22-1271), and&#160;the Innovation &#38; Technology Commission (Health@InnoHK).

This prospective, single-center, randomized, controlled clinical study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (XYFY2021-KL124-02). The study started in July 2021 and will continue until July 2023; 60 patients were recruited in this experiment. All patients signed an informed consent that allowed the researchers to use their clinical materials and biological data.
1. Recruitment of patients
<ol>
	<li>Inclusion criteria:
	<ol>
		<li>Ensure that the patients' ages are between 18 years and 80 years (inclusive), regardless of gender.</li>
		<li>Ensure that the patients with type 2 diabetes and diabetic foot ulcers meet the 1999 WHO diagnostic criteria14 and have a glycated hemoglobin (HbA1c) level ≤10% as detected during the screening period or within 3 months prior to randomization.</li>
		<li>Confirm that the ankle-brachial index15 of the target limb is at least 0.8 without intermittent claudication.</li>
		<li>Ensure that each patient's ulcer has the following characteristics: 
		Grade 1 or grade 2 according to the Wagner grading system16 for ulcers. 
		Location in the foot, ankle, or front shin. 
		Cross-sectional area after debridement of 2-5 cm2. 
		​No pus or necrotic substance visible to the naked eye at least 4 weeks before randomization.</li>
		<li>Do not include patients undergoing routine treatment of other wounds in the study.
		<ol>
			<li>If multiple wounds are present, select the wound that meets the inclusion criteria and has the largest intervention and assessment area.</li>
			<li>If two or more wounds are similarly large, select the one with the most severe grade.</li>
			<li>If there are two or more wounds with the same area and grade, select the one with the longest wound duration.</li>
		</ol>
		</li>
		<li>Participation in this clinical study is voluntary. Ensure that the patients cooperate with the physicians conducting the study and sign an informed consent form.</li>
	</ol>
	</li>
	<li>Exclusion criteria:
	<ol>
		<li>Exclude patients with clear surgical indications: vascular occlusion, bone exposure, abscess, osteomyelitis.</li>
		<li>Exclude patients with revascularization or angioplasty within 3 months prior to enrollment.</li>
		<li>Exclude patients with hepatic impairment; specifically, exclude patients with ALT (aspartate aminotransferase) and AST (alanine aminotransferase) levels three times higher than the upper limit of normal.</li>
		<li>Exclude patients with blood creatinine levels more than two times above the upper limit of normal; serum albumin &lt;2.0 g/dL; immunosuppressive drug treatment; various malignant tumors; and pregnancy, breastfeeding, or a recent birth plan.</li>
		<li>Exclude patients with contraindications, allergies, or known allergies to any component of stem cell preparation products.</li>
		<li>Exclude patients in other situations that cause the investigator to believe the patient should not participate in this study:
		<ol>
			<li>Exclude patients if it is discovered after admission that they do not meet the most important admission criteria.</li>
			<li>Exclude patients with serious adverse reactions, patients who request to withdraw from the study, and patients whose legal guardian requests for them to withdraw from the study.</li>
			<li>Exclude patients with a lack of medication or effective post-enrollment observational data.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Randomization and blinding
	<ol>
		<li>Randomize the patients recruited from the outpatient department of the Affiliated Hospital of Xuzhou Medical University on a 1:1 basis into the stem cell therapy group and the conventional wound treatment group.</li>
		<li>Conduct a double-blind trial for the treatment. Ensure a third party measures the wound area of each patient.</li>
	</ol>
	</li>
</ol>
2. Preoperative treatment
<ol>
	<li>Perform routine pretreatment examinations for the patients after enrollment, including a routine blood test, urinalysis, a routine stool assessment, a biochemical function assessment, a coagulation function assessment, virology, etc. Ensure that patients are followed up in the same hospital to ensure the accuracy of the tests.</li>
	<li>Include patients who meet the inclusion criteria and have signed the written informed consent. Assign each subject randomly to either the stem cell therapy group or the conventional wound treatment group in a 1:1 ratio using a proportionate sampling technique.</li>
</ol>
3. Treatment procedures
NOTE: Patients in both groups receive systematic routine wound dressing changes every 3 days. For the stem cell treatment group, patients receive local injections of stem cells four times (on day 1, day 8, day 15, and day 22 after enrollment). In the conventional wound treatment group, the patients are treated with silver ion dressing four times (on day 1, day 8, day 15, and day 22 after enrollment). The specific steps are as follows.
<img alt="Wound treatment flowchart comparing conventional methods and HUCMScs injection process." class="xfigimg" src="/files/ftp_upload/65045/65045fig01.jpg" data-altupdatedat="1788304762000" data-alt="Figure 1"> 
Figure 1: Treatment process. In each group, 30 patients will undergo treatment strictly following the protocol described in this study. <a href="https://www.jove.com/files/ftp_upload/65045/65045fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<ol>
	<li>Stem cell therapy group
	<ol>
		<li>After locally disinfecting the wound with povidone-iodine and removing the necrotic tissue from the wound surface with surgical scissors, use a syringe to aspirate 50 mL of physiological saline to clean the wound surface inside and out.</li>
		<li>Measure the wound area using the sterile foil edge hook method17. Apply the sterile film transparent dressing with its coordinate grid to the wound surface, and outline the shape of the wound surface along its edge with a marker. Calculate the wound area according to the area of each coordinate grid of the film.</li>
		<li>Inject the human umbilical cord mesenchymal stem cells (2 x 105 cells/cm2; 0.4 mL/cm2) into the periphery and the base of the wound (injection spacing: 0.75 cm; injection volume: 0.1 mL/site). 
		NOTE: The number of injections for each patient depends on the wound area.</li>
		<li>Trim the sterile dressing to appropriate size, cover it over the wound surface, and then bandage it.</li>
	</ol>
	</li>
	<li>Conventional wound treatment group
	<ol>
		<li>After locally disinfecting the wound with iodophor and removing the necrotic tissue from the wound surface with surgical scissors, use a syringe to aspirate 50 mL of physiological saline to clean the wound surface inside and out.</li>
		<li>Measure the wound area using the sterile foil edge hook method17. Apply the sterile film transparent dressing with its coordinate grid to the wound surface, and outline the shape of the wound surface along its edge with a marker. Calculate the wound area according to the area of each coordinate grid of the film.</li>
		<li>Trim the silver ion dressing to an appropriate size, cover it over the wound surface, and then bandage it.</li>
	</ol>
	</li>
</ol>
<img alt="Wound dressing on foot for medical care, showcasing transparent adhesive and protective application." class="xfigimg" src="/files/ftp_upload/65045/65045fig02.jpg" data-altupdatedat="1788304762000" data-alt="Figure 2"> 
Figure 2: Schematic diagram of foot ulcer area measurement. <a href="https://www.jove.com/files/ftp_upload/65045/65045fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Stem cell injection diagram; formula 2×10^5 cells/cm² for wound treatment on foot." class="xfigimg" src="/files/ftp_upload/65045/65045fig03.jpg" data-altupdatedat="1788304762000" data-alt="Figure 3"> 
Figure 3: Schematic of the human umbilical cord mesenchymal stem cell injection. <a href="https://www.jove.com/files/ftp_upload/65045/65045fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
4. Observation indicators
<ol>
	<li>Obtain the demographic data of the subjects.</li>
	<li>Record the concomitant treatments; specifically, record the wound status (location, area, depth, infection, and ischemia), the wound healing rate, the healing time, and complications.</li>
	<li>Perform laboratory tests. Take the wound secretion for swabs and bacteriological culture. Conduct routine blood tests and tests for liver and kidney function.</li>
</ol>
5. Follow-up
<ol>
	<li>Examine the patients on the first day of therapy and during the follow-up visits 15 days and 30 days after the last therapy.</li>
	<li>Conduct follow-ups using both outpatient and telephone appointments to record the treatment effects, condition changes, recovery situation, and current living status.</li>
</ol>
6. Outcomes efficacy assessment
<ol>
	<li>Conduct the clinical evaluation according to the following criteria.
	<ol>
		<li>Calculate the primary outcome index: 
		The 30 day wound healing rate = (original wound area − unhealed wound area at 30 days)/original wound area × 100%.</li>
		<li>Calculate the secondary outcome index
		<ol>
			<li>Wound healing time: Define the time of wound closure as the time at which the wound is completely re-epithelialized.</li>
			<li>Calculate the complete healing rate: 
			The complete healing rate = the number of complete healed cases/the total number of cases × 100%</li>
		</ol>
		</li>
		<li>Calculate the surgical intervention rate: 
		Surgical intervention rate = the number of surgical interventions/the total number of cases × 100%. 
		NOTE: Subjects who underwent one of the following procedures are recorded as patients with surgical interventions: debridement and drainage, skin grafting, adjacent skin flap, distal skin flap, non-anastomotic skin flap, and amputation.</li>
		<li>Perform the bacterial culture18 according to the standard clinical inspection procedures, and record bacterial culture results of ≥1 pathogen as positive. Calculate the pathogen positive rate: 
		Pathogen positive rate = the number of cases detected pathogen positive/the total number of cases × 100%.</li>
	</ol>
	</li>
</ol>
7. Safety procedures
<ol>
	<li>In the case of an adverse event (any disease, new symptoms, signs, or laboratory examination abnormalities or the deterioration of the original symptoms and signs occurring during the stem cell clinical research, regardless of whether the event is related to the clinical research drug or not), take the necessary measures for treatment and rescue.</li>
	<li>Track and investigate all the adverse events and the treatment process, and record the results in detail until properly resolved or until the condition is stable. If a test is abnormal and has clinical significance, follow it up until it returns to normal.</li>
</ol>

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</ol>

The authors have no conflict of interest to declare.

DFUs are a major global public health problem and a key cause of lower limb amputations and poor health-related quality of life19,20. At present, clinical management is still dominated by conventional debridement, hyperbaric oxygen therapy, vacuum sealing drainage (VSD), and conservative management. Larger wounds often require the transplantation of skin and skin flaps. Many patients suffer from long-term and repeated illnesses that cause severe physical and ment...

Diabetes mellitus is a disease that affects individuals worldwide, and the World Health Organization (WHO) predicts that the number of people with diabetes mellitus will increase from 285 million in 2010 to 439 million in 20301. Diabetic foot ulcers (DFUs) are one of the most serious complications of diabetes and are main contributors to non-traumatic lower-extremity amputations across the world2,3,4,5.
Recently, stem cells have flourished as a therapy due to their pluripotency, self-renewal, and ability to promote the secretion of regenerative cytokines6,7. A previous clinical experiment showed that fat-derived stem cell gels had a positive effect on the treatment of foot ulcers in chronic diabetes8. The authors verified the effectiveness of using stem cells to treat diabetic wounds in 59 patients. At week 12, the rate of complete wound closure in the treatment and control groups was 82% and 53%, respectively, which indicates that stem cells are effective for the treatment of refractory diabetic wounds. Overall, the ability of stem cells to regenerate, replace, repair, and differentiate has given infinite hope to the life science community9.
In 2008, Dulchavsky et al.10 used grafts containing autologous bone marrow stromal cells (BMSCs) to treat 20 cases of non-healing wounds of different causes. Histological examinations showed that the skin wounds of 18 patients were completely re-epithelialized. Similarly, the use of allogeneic non-diabetic mesenchymal stem cells (MSCs) in gelatin scaffolds for the treatment of nonunion diabetic wounds can promote angiogenesis, increase re-epithelialization, and reduce the ulcer area11. However, there are few cases of stem cell treatment of diabetic foot wounds in domestic and foreign clinical research studies; most are only case reports or exploratory clinical research lacking a strict experimental design, and there are few large samples with good design or randomized controlled clinical trials. As stem cells are not common drugs or biological products, the preparation methods and quality controls differ between studies. Data from one study may not fully reflect the safety of all stem cells from the same species. Therefore, we further summarized the relevant basic research and preclinical experiments with human umbilical cord mesenchymal stem cells (HUCMSCs) and systematically evaluated the safety and efficacy of their clinical application. On this basis, the injection of mesenchymal stem cells from the human umbilical cord to repair diabetic foot wounds was developed as a treatment. This study aims to verify the efficacy and safety of stem cell repair of diabetic foot wounds in clinical use.
In summary, stem cell therapy has a broad spectrum of applications and great potential and represents a promising new medical treatment method. With the continued support of the National Natural Science Foundation of China (No. 81571901, No. 81501671, and No. 82172224), we conducted a series of studies on the treatment of diabetic wounds with HUCMSCs. We have published more than 20 related articles in the Journal of Investigative Dermatology, Stem Cell Research and Therapy, and Cell Death and Disease and have applied for three national invention patents, thus accumulating a large foundation of research12,13. Here, we provide a standard approach to evaluate the injection of HUCMSCs for diabetic foot wound repair. This standard procedure has been approved by Chinese drug clinical trials (Trial registration number: Chinese drug clinical trials: MR-32-21-015759, [Initial Release: 10/20/2021]).

<table><tbody><tr><td>Silver Iin Wound Dressing</td><td>Shandong Cheerain Medical Co.,Ltd.&amp;nbsp;</td><td>20152640521</td><td>Sterile silver ion dressing for medical use (Type F) 10 cm x 10 cm</td></tr><tr><td>Human Umbilical Cord Mesenchymal Stem Cells Injection</td><td>Shandong Qilu Cell Therapy Engineering Technology Co., Ltd.</td><td>32183185-X</td><td>Main components: human umbilical cord mesenchymal stem cells. Pharmacological effect: non-specific immunomodulator can enhance the secretion of growth factor, vasoactive factor and anti-inflammatory factor, improve the anti infection ability of human body, eliminate inflammation, promote angiogenesis and ulcer healing.</td></tr><tr><td>Sterile mesh film transparent dressing</td><td>Smith &amp;amp; Nephew</td><td>20162644490</td><td>Sterile mesh film transparent dressing (used for wound area measurement) 6 cm x 7 cm</td></tr></tbody></table>

prospective, randomized, and controlled study of a human umbilical cord mesenchymal stem cell injection for treating diabetic foot ulcers

Prospective, Randomized, and Controlled Study of a Human Umbilical Cord Mesenchymal Stem Cell Injection for Treating Diabetic Foot Ulcers

With the development of society and the economy, the incidence of diabetic foot ulcers continues to increase. Currently, conventional debridement with dressing changes, hyperbaric oxygen, and vacuum sealing drainage are the main conservative treatments in clinical practice, and large wounds often require skin grafts or skin flap grafts. However, the treatment effects are not ideal, and many complications exist. Due to its complex pathogenesis, long treatment time, significant associated difficulties, and high disability rate, diabetic foot ulcers cause a heavy burden to patients, society, and medical care. According to our previous study, the pharmacological effects of human umbilical cord blood stem cells include nonspecific immune regulation; increased secretion of growth factors, vasoactive factors, and anti-inflammatory factors; enhanced anti-infectious ability of the human body; elimination of inflammation; and promotion of angiogenesis and ulcer healing. These effects suggest stem cells may be useful as an autologous or allogeneic treatment for refractory wounds. Therefore, we are conducting a clinical trial to treat refractory diabetic wounds with human umbilical cord stem cells in our clinic for diabetic foot ulcer patients who meet the inclusion criteria.

At present, our research is still in the patient recruitment phase, and we have now completed three patients in the HUCMSCs treatment group and three patients in the control group with silver ion dressings, giving a total of six patients with chronic diabetic foot wounds. The average size of the ulcer area of a patient in the HUCMSCs treatment group was 3.5 cm2, and this was reduced to 2.6 cm2, 1.8 cm2, and 1.25 cm2 on the 8th, 15th, and 22nd days after treatment with HUCMSCs (...

The present protocol describes a prospective, randomized, controlled clinical study that evaluates a human umbilical cord mesenchymal stem cell injection for the treatment of chronic diabetic foot ulcers.

With the development of society and the economy, the incidence of diabetic foot ulcers continues to increase. Currently, conventional debridement with ...

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Research

JoVE Journal

Bioengineering

The surgical procedure for delivery of embryonic stem cell-derived endothelial cells to the ischemic hindlimb is demonstrated, with non-invasive tracking by bioluminescence imaging.

Embryonic Stem Cell-Derived Endothelial Cells for Treatment of Hindlimb Ischemia

Adipose-derived stem cells (ASCs) are easily isolated and harvested from the fat of normal rats. ASC sheets can be created using cell-sheet engineering and can be transplanted into Zucker diabetic fatty rats exhibiting full-thickness skin defects with exposed bone and then covered with a bilayer of artificial skin.

Creation and Transplantation of an Adipose-derived Stem Cell (ASC) Sheet in a Diabetic Wound-healing Model

Here, we present a protocol for the dissection of human umbilical cord (UC) and fetal placenta sample into cord lining (CL), Wharton's jelly (WJ), cord-placenta junction (CPJ), and fetal placenta (FP) for the isolation and characterization of mesenchymal stromal cells (MSCs) using the explant culture technique.

Isolation and Characterization of Mesenchymal Stromal Cells from Human Umbilical Cord and Fetal Placenta

Murine studies in models of colonic inflammation have demonstrated that a small percentage (1 - 5%) of mesenchymal stem cells (MSC) injected intravenously or intraperitoneally home to the inflamed colon1,2. This study shows that ultrasound-guided intracardiac injections of MSCs result in increased localization to the intestine.

Ultrasound-guided Intracardiac Injection of Human Mesenchymal Stem Cells to Increase Homing to the Intestine for Use in Murine Models of Experimental Inflammatory Bowel Diseases

This paper describes the preparation and evaluation of umbilical cord matrix-derived mesenchymal stem cells spheroids with a bilateral patellar tendon defect model in a rat. This model was associated with an acceptable morbidity and was found to detect differences between untreated and treated tendons, and between the two treatments tested.

Evaluation of Stem Cell Therapies in a Bilateral Patellar Tendon Injury Model in Rats

Human umbilical cord (UC) can be obtained during the perinatal period as a result of preterm, term, and postterm delivery. In this protocol, we describe the isolation and characterization of UC-derived mesenchymal stem cells (UC-MSCs) from fetuses/infants at 19-40 weeks of gestation.

Isolation and Characterization of Human Umbilical Cord-derived Mesenchymal Stem Cells from Preterm and Term Infants

Adipose tissue-derived mesenchymal stem cells (Ad-MSCs) can be a potential source of MSCs that differentiate into insulin-producing cells (IPCs). In this protocol, we provide detailed steps for the isolation and characterization of rat epididymal Ad-MSCs, followed by a simple, short protocol for the generation of IPCs from the same rat Ad-MSCs.

Isolation of Rat Adipose Tissue Mesenchymal Stem Cells for Differentiation into Insulin-producing Cells

The streptozotocin-induced diabetic wound model in male SD rats is currently the most widely used model for studying wound healing in type I diabetes mellitus. This protocol describes the methods used to construct this model. It also presents and addresses potential challenges and examines the progression and angiogenic characteristics of diabetic wounds.

A Protocol for Constructing a Rat Wound Model of Type 1 Diabetes

This study presents two crucial experimental techniques: the construction of a murine wound model for assessing wound closure and the preparation of single-cell suspensions from murine skin to preserve cellular viability.

Mouse Wound Models and Preparation of Single-Cell Suspensions

The isolation of BAMBIhighMFGE8high MSCs, one of the three main subgroups constituting heterogeneous human UC-MSCs, is helpful for fully understanding the characteristics and functions of this subtype for its future application to improve clinical efficacy in specific diseases. Here, we present a method for sorting BAMBIhighMFGE8high UC-MSCs.

Isolation of Human BAMBIhighMFGE8high Umbilical Cord-Derived Mesenchymal Stromal Cells

Learn a standardized protocol for treating diabetic foot ulcers using human umbilical cord mesenchymal stem cell injections. This randomized controlled study evaluates safety, effectiveness, and wound healing outcomes.

Prospective, Randomized, and Controlled Study of a Human Umbilical Cord Mesenchymal Stem Cell Injection for Treating Diabetic Foot Ulcers (Video) | JoVE Journal

Prospective, Randomized, and Controlled Study of a Human Umbilical Cord Mesenchymal Stem Cell Injection for Treating Diabetic Foot Ulcers

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