CLTI/CLI is not always the end of the road: this review maps the emerging alternatives that may help selected “no-option” patients avoid or delay amputation, from cell and gene therapy to venous arterialization, retrograde access, and adjunctive pharmacology. The full paper shows where the evidence is clinically promising, where it remains experimental, and which strategies may realistically enter limb-salvage practice next.
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Abstract: This paper aims to synthesize evidence on alternative therapeutic strategies for chronic limb-threatening ischemia (CLTI), historically termed critical limb ischemia (CLI), including cell-based regenerative medicine, gene therapy, nanomedicine, and novel endovascular or pharmacological approaches, focusing on their safety, efficacy, and potential for limb preservation. The review utilises 148 original studies with 27470 total participants (topic deduplicated ΣN). Across the mapped evidence, autologous regenerative strategies emerged as one of the most prominent alternative-therapy signals for no-option CLI/CLTI, with bone marrow-derived mononuclear cells and mesenchymal stem cells associated with therapeutic angiogenesis, wound healing, rest-pain reduction, ABI/TcPO2 improvement, and long-term safety or functional signals. Buerger's disease cohorts further supported this pattern, including a reported 10-year amputation-free survival of 85.3% versus 40% with bone marrow mononuclear cells plus aspirin. Across the wider mechanical and device-based alternative-therapy map, deep venous arterialization, retrograde pedal access, and below-the-knee drug-eluting stenting were recurrent limb-salvage alternatives, including reported limb-salvage signals of 71% and 93.8% in selected cohorts. Pharmacological adjuncts such as cilostazol-based regimens, rivaroxaban-based combinations, and low-dose rivaroxaban plus aspirin after peripheral arterial reconstruction, together with gene therapy targeting VEGF, HGF, ANG1, and HIF-1α, indicated additional avenues for limb preservation and pain control after failed, unfeasible, or completed revascularization. The map also highlights that nanomedicine, engineered cell products, and biomaterial-based delivery platforms remain largely preclinical, and that high-risk subgroups such as ESRD and physiologically impaired patients may not derive functional benefit from revascularization alternatives. Practically, these signals support a tiered approach in which advanced endovascular techniques, cell- and gene-based angiogenic therapies, and adjunctive pharmacotherapy are considered before amputation in selected no-option patients. Future research should prioritize larger multicenter trials with standardized limb-salvage and wound-healing endpoints, manufacturing and karyotype quality controls for autologous cell products, and first-in-human translation of nanomedicine and next-generation gene-delivery platforms to clarify their place within the alternative-therapy landscape.
Final search date and database lock: 2026-05-03 23:40:54 CEST
Plan: Pro (expanded craft tokens; source: Semantic Scholar)
Source: Semantic Scholar
Total Abstracts/Papers: 3925
Downloaded Abstracts/Papers: 1000
Included original and non-original Abstracts/Papers (all): 219
Included original Abstracts/Papers (Vote counting by direction of effect): 148
Reference Index (links used in paper): 144
Total participants (topic deduplicated ΣN): 27470
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