The severe restriction of blood flow in lower body proximities has consequences that are far more complicated than occasional discomfort. Critical Limb Ischemia (CLI), now known as Chronic Limb-Threatening Ischemia, is an advanced form of peripheral artery disease (PAD). The condition is characterized by plaque buildup (atherosclerosis) in arteries. The condition leads to intense rest pain, non-healing wounds, or severe tissue damage.
In the severe form of Critical Limb Ischemia, limb amputation is required. The conventional treatment can potentially manage the condition, yet they do not provide a complete solution. The emergence of regenerative medicine has caught the attention of researchers and clinicians in the past decade. The intent is not to just manage the artery blockage, but to make the changes at the cellular and molecular level.
Critical Limb-Threatening Ischemia: Pathophysiology
Critical limb ischemia is mediated by plaque development at artery walls that leads to macro and microvascular dysfunction. The pathophysiology of CLI development is complex and not completely understood. The studies revealed the cumulative action of inflammatory molecules, hyperlipidemia, thrombotic factors, and immune response triggers CLI development. In the intimal layer of arteries, lipoprotein accumulation occurs, which leads to endothelial damage. It recruits immune response, macrophages and lymphocytes accumulate at the injury site and consume oxidised lipids. As a result, fatty streak development occurs that progresses into plaque, resulting in artery narrowing. It severely blocks blood flow to the affected region, cutting off the oxygen flow critically. The poor blood circulation delays wound repair and leads to progressive tissue necrosis.
What are the Symptoms of CLI?
The CLI Symptoms Include:
- Persistent foot or leg pain
- Pain elevates at night or is ‘resting pain’
- Non-healing ulcers and wounds
- Tissue damage or death leads to gangrene
- Increases the risk of limb amputation
Critical Limb Ischemia ICD 10 Classification
CLI does not appear under a single ICD10 code. The classification considers atherosclerosis, vessel type, affected leg and clinical symptoms. Critical Limb Ischemia ICD 10 Classification enables tracking of symptoms, injuries, causes, or death. The critical factors include:
Affected Vessel
- 170: atherosclerosis
- 170.2: Native arteries
- 170.3, 170.4, 170.5: Bypass graft
- 170.6, 170.7: Non-autologous graft/stent
Affected Side
- Right
- Left
- Bilateral
Clinical Manifestation
- 170.221 (Right), 170.222 (Left), 170.229 (Non-specific): Rest Pain
- 170.231 (Right), 170.232 (Left), 170.239 (Non-specific): Ulceration
- 170.261 (Right), 170.262 (Left), 170.269 (Non specific): Gangrene
What are the Current Treatment Regimes?
Critical Limb Ischemia Treatment intends to restore blood flow and boost wound healing. The tissue damage that isn’t salvageable might require surgery involving toe removal or limb amputation. The conventional treatment regimes involve:
Medication
- Anticoagulants or antiplatelets (lower risk of blood clots)
- Statins (reduce bad cholesterol and lower risk of atherosclerosis)
- Antihypertensive medication (lower blood pressure)
- Anti-diabetic drug
Leg Revascularization
- Surgical procedure to enable adequate blood flow in the legs
- Not suitable for patients with gangrene or irreversible tissue damage
Venous Arterialization
- Surgical procedure connecting arteries to veins
- Enables the flow of oxygen-rich blood in the affected foot or leg area
Wound Care
- Removal of dead or damaged tissue (debridement)
- Prevent further tissue damage
- Antibiotics are prescribed to prevent further bacterial infection
Amputation
- Last resort of care involves surgical removal of the limb or foot
- Prosthetics are recommended for the patient’s recovery
Lifestyle Modification
- Dietary intervention, consumption of a balanced diet with high protein, fiber, and low fat
- Quit smoking or substance use
- Use of orthotics or custom-made shoes to release pressure on certain foot parts promotes wound healing.
How are Stem Cells Transforming CLI Management?
Stem cells for Critical Limb Ischemia involve the injection of cultured cells into the damaged or affected area to promote faster healing. Stem cells possess regenerative potential that enables the development of naive cells and the repair of damaged cells. Researchers have widely explored the mesenchymal stem cells due to their regenerative efficacy and paracrine signalling.
Stem cells in critical limb ischemia treatment involve the following mechanisms:
Blood Vessel Regeneration
- MSCs possess regenerative capability; the cells can differentiate into specific cell types, including endothelial cells and blood vessels
- Naive cell regeneration replaces the damaged or dead cells
- Blood vessel regeneration promotes adequate blood flow, reduces ischemic areas
Angiogenesis Stimulation
- MSCs release paracrine factors, including angiogenic molecules (VEGF, FGF)
- Stimulates angiogenesis, enabling restoration of vascular networks
- Promote adequate blood, oxygen, and nutrient supply to ischemic tissues
- Promotes wound healing
Activation of Repair Mechanism
- Releases cytokines and growth factors, boosts the body’s natural healing mechanism
- Formation of new cells and blood vessels promotes restoration of the tissue’s original function
Immunomodulation & Anti-inflammation
- MSCs modulate immune response and regulate macrophage or T-cell response
- Releases anti-inflammatory cytokines, neutralizes the effect of pro-inflammatory signals
- Fosters a conducive microenvironment for tissue healing
What Do Clinical Studies Suggest So Far?
Currently, stem cell research and clinical application are at an early stage. Early investigation revealed the safety and tolerance of stem cells among CLI patients. The evidence reflects:
- Improvement in tissue perfusion, angiogenesis, and microvascular circulation. Enables restoration of adequate blood supply in ischemic limbs
- Improved wound healing, ulcer closure and reduced ischemic rest pain. Improved quality of life for the patient
- Lowered incidences of limb amputation among patients who are not suitable for conventional revascularization procedures [1]
- Distinct stem cell types, including MSCs, bone marrow-derived stem cells, and peripheral blood-derived progenitor cells, are used by researchers. They release growth factors and support the repair mechanism.
- The majority of the studies reported intact safety profiles and negligible adverse events [1, 2]
Current Research Challenges
Despite promising evidence, the findings of stem cells for CLI are inconsistent across studies. There is variation in cell source, dosage, delivery techniques, patient selection criteria, etc. The future focus must include:
- A large-scale clinical trial on a larger population-based study to establish long-term safety
- Standardization of therapeutic protocols and developing standard guidelines for clinical applications
- Determination of predefined patient selection criteria
What are the Key Considerations?
Patients considering stem cells for Critical Limb Ischemia Treatment must understand:
- Therapy outcome varies among individuals. The outcome depends on various factors like stem cell source, isolation procedure, administration mode, and the individual’s response to the treatment.
- Stem cells used must be of superior quality.
- Choose a renowned clinic and experienced clinicians, gather information related to the treatment procedure and possible outcome
- The progress occurs gradually; set clear expectations before opting for the treatment
- Clinicians often combine regenerative medicine with conventional treatment options to gain an optimal outcome
*Advancells, India, is a renowned stem cell manufacturing laboratory that supplies clinical-grade stem cells for various chronic diseases, including CLI
Conclusion
Critical Limb Ischemia treatment takes a considerable amount of time. It involves the involvement of a multidisciplinary team including surgeons, dieticians, podiatrists, physical therapists, etc. The emergence of stem cell therapy has laid new hope in CLI treatment. The therapeutic outcome remains promising due to their ability to induce regeneration and repair mechanisms from within. This can potentially reduce amputation risk gradually.
References
- Rigato M, Monami M, Fadini GP. Autologous cell therapy for peripheral arterial disease: systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies. Circulation Research. 2017;120(8):1326-1340.
- Ganjehcheh F, et al. Stem cell therapy in peripheral artery disease and chronic limb-threatening ischemia: current evidence and future directions. Stem Cell Research & Therapy. 2024;15:292.
FAQ’s
Q- Is Stem Cell Therapy Approved for Critical Limb Ischemia?
No, stem cell therapy is not approved as a standalone treatment for CLI. Currently, stem cell therapy is implied as a supportive option along with conventional treatment options and not as an independent option.
Q- Do Stem Cells Help Improve Blood Flow in Ischemic Limbs?
Yes, stem cells release various cytokines and growth factors that support angiogenesis, that is, the development of new blood vessels. It enables adequate blood, oxygen and nutrient flow to the ischemic limb. It supports healing mechanisms.
Q- Can Stem Cell Research Reduce the Risk of Amputation in CLI Patients?
Preclinical and clinical evidence revealed reduced amputation risk with stem cell therapy among CLI patients. The patients not suitable for conventional treatment options are especially benefited by the approach. However, the study is still at an early stage.
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