What is the efficacy and safety of human placental extract with umbilical cord stem cells based on human Randomized Controlled Trials (RCTs)?

Efficacy and Safety of Human Placental Extract with Umbilical Cord Stem Cells Based on Human RCTs

Consider the use of placental-derived products as an adjunctive therapy to standard care for wound healing in diabetic foot ulcers only when standard care alone has failed, as there is limited evidence supporting their efficacy and safety from human RCTs. 1

Evidence on Placental-Derived Products for Wound Healing

Efficacy in Diabetic Foot Ulcers

• The International Working Group on the Diabetic Foot (IWGDF) 2023 guidelines provide a conditional recommendation with low-quality evidence for using placental-derived products as adjunct therapy for diabetic foot ulcers when standard care alone has failed 1
• Multiple placental-derived products have been studied, including:
  • Dehydrated amnion/chorion grafts 1
  • Dehydrated human amniotic membrane (dHAM) 1
  • Cryopreserved placental membrane 1
  • Dehydrated human umbilical cord 1

Clinical Outcomes

• Studies suggest improved absolute wound healing at timepoints between 4-20 weeks compared to standard care 1
• Reduced time to healing has been reported in studies, though many were assessed as having high risk of bias 1
• Percentage area reduction was improved in five studies, though two had high risk of bias 1
• No significant difference in new infection rates was reported 1
• No evidence of impact on amputation rates was found 1
• No studies reported quality of life outcomes or maintenance of function 1

Limitations of Current Evidence

• Most studies were considered at high risk of bias 1
• Few definitive studies were blinded to patients or caregivers 1
• Only three studies were assessed as being at low risk of bias, with only one being double-blinded (a small pilot/feasibility study) 1
• Short-term nature of most studies limits conclusions about long-term outcomes 1
• Patients with significant peripheral arterial disease were often excluded from studies 1

Cost Considerations

• Two papers reported the cost of intervention per healed ulcer:
  • Over $2,000 for dehydrated human amniotic membrane 1
  • Over $3,000 for dehydrated umbilical cord products 1
• Formal cost-effectiveness data was only published in one post-hoc analysis of a study judged at high risk of bias 1
• Resource use may be lower than other skin substitutes in some healthcare systems 1
• Cost implications may reduce equity in lower-resource healthcare systems 1

Specific Types of Placental Products

Amniotic Membrane Products

• A well-designed single-blind RCT showed higher incidence of ulcer closure (62% vs 21%, p<0.001) after 12 weeks with weekly application of cryopreserved amniotic membrane allograft compared to standard care 1
• A three-arm RCT comparing bioengineered skin substitute, amniotic membrane product, and collagen-alginate dressing found highest healing rates within 12 weeks for the amniotic membrane product, though outcomes were unblinded 1

Umbilical Cord Products

• A single-blind study of an umbilical cord product showed significant improvement in healing compared to usual care, though neither patient nor investigator was blind to treatment allocation 1

Stem Cell Considerations from Umbilical Cord

Characteristics of Umbilical Cord Stem Cells

• Human umbilical cord and placenta are non-invasive, primitive, and abundant sources of mesenchymal stromal cells (MSCs) that pose no ethical concerns 2
• Umbilical cord contains multiple stem cell populations capable of forming different cell types 3
• These cells display surface markers similar to bone marrow-derived MSCs, including CD29, CD44, CD73, CD90, and CD105 2

Potential Applications

• Umbilical cord stem cells have shown potential for both hematopoietic reconstitution and non-hematopoietic differentiation 4
• They can differentiate into adipogenic, chondrogenic, and osteogenic lineages, indicating multipotency 2
• The cord-placenta junction (CPJ) appears to be the most potent anatomical region, yielding cells with greater proliferation and self-renewal capacities 2

Safety Considerations

Umbilical Cord Milking Studies (Related Safety Data)

• Studies on umbilical cord milking (a different application) found no difference in mortality compared to immediate cord clamping (OR, 0.76; 95% CI, 0.25–2.29) 1
• No evidence of adverse effects in preterm infants <37 weeks' gestation or their mothers after umbilical cord milking compared with immediate cord clamping 1
• However, low-certainty evidence suggests increased severe intraventricular hemorrhage after intact-cord milking compared with deferred cord clamping in infants <28 weeks' gestation 1

Clinical Application Guidance

When to Consider Use

• Consider placental-derived products only after standard care has failed to reduce ulcer size 1
• Most suitable for diabetic foot ulcers without significant peripheral arterial disease 1
• Not recommended for routine use in all wound types due to limited evidence 1

Practical Considerations

• Cryopreserved products require special storage and defrosting time 1
• Dehydrated products are easier to store and handle but contain growth factors without living cells 1
• Weekly application may be required, which has significant cost and resource implications 1

Knowledge Gaps and Future Research Needs

• Long-term outcomes including quality of life and function are not well studied 1
• Formal cost-effectiveness analyses are needed 1
• Optimal patient selection criteria are not established 1
• The number of specialized cells capable of undergoing differentiation into non-hematopoietic cells remains low, limiting clinical development 4