Enhancing skin-implant integration in lower-limb transcutaneous prostheses: From interface biology to bioactive, antimicrobial and cell-based strategies.

Transcutaneous prosthetic systems, which directly connect an external limb prosthesis to the skeleton, offer substantial biomechanical and clinical advantages over conventional socket-based devices. By eliminating the soft tissue loading inherent to the socket interfaces, these systems enable improved load transfer, comfort, and more natural sensory feedback through direct skeletal attachment. However, their widespread clinical adoption remains limited by complications at the skin-implant interface, including infection, marsupialization, and epithelial down-growth.Advances in surface engineering, particularly nanoscale modifications, have demonstrated a critical capacity to both promote host cell adhesion and direct macrophage polarization, thereby addressing epithelial sealing and chronic inflammation. Bioactive coatings incorporating extracellular matrix proteins or adhesion peptides have been designed to replicate dermal-epidermal interactions and reinforce epithelial anchorage. In parallel, antimicrobial strategies employing antibiotics, peptides, or metal-based coatings have been developed to counteract bacterial colonization of the stoma. Moreover, cell-based therapies using fibroblasts and mesenchymal stem cells have shown promise in supporting dermal integration and modulating local inflammation. Despite these advances, durable and infection-resistant skin-implant integration remains unresolved, indicating that long-term clinical success will require integrated, multifunctional interfaces capable of simultaneously supporting soft-tissue sealing, infection control, immunomodulation and mechanical stability. The translational potential of this article: The development of transcutaneous prostheses designed to enhance skin-implant integration in lower-limb amputees holds substantial translational promises, with implications that extend from individual patient outcomes to broader healthcare systems and biomedical innovation pipelines. Although osseointegrated prosthetic systems have demonstrated improved mobility and enhanced comfort, compared with traditional socket-based devices, their widespread clinical adoption remains limited by complications at the percutaneous interface. Addressing these challenges through bio-hybrid interface creates a realistic pathway toward an infection-resistant and durable skin attachment.From a translational perspective, this strategy is gaining increasing interests due to its practical feasibility: several of its core elements, including surface-modified titanium, antimicrobial coatings, and bioactive agents, are supported by existing regulatory pathways. This enables stepwise innovation within well-defined approval frameworks without the need to create entirely new regulatory categories.Next-generation implants could build upon clinically accepted materials while incorporating advanced surface functionalities that promote epithelial sealing, dermal integration, and controlled immune modulation. Smart, bioresponsive surfaces capable of releasing antimicrobial or anti-inflammatory agents in response to bacterial colonization further strengthen the clinical value proposition by directly addressing infection risk, one of the primary causes of implant failure and revision surgery. Reducing these complications, improving the biological seal at the skin-implant junction, is not merely a solution to a complication: it is an initial enabling technology for the next generation of smart prostheses, that would integrate sensors and neural communication systems, and decrease long-term healthcare costs associated with hospitalizations, antibiotic therapy, and surgical revisions, thereby reducing the overall cost of healthcare system.Successful clinical translation will depend on multidisciplinary collaboration, robust preclinical modelling of the skin interface, and carefully designed clinical trials that evaluate both biological integration and functional outcomes. Enhanced skin-implant integration could shift transcutaneous prostheses from a niche intervention to a broadly adopted standard of care, redefining long-term rehabilitation strategies for individuals living with limb loss.