Safety and efficacy of subcutaneous and intradermal polycaprolactone / carboxymethyl cellulose gel injections

• Dilution triggers rapid PCL microsphere hydrolysis, altering rheology for dermal delivery. • First evidence that intradermal diluted PCL/CMC enhances collagen I/III/XVII regeneration. • High-dilution (1:5) PCL/CMC shows optimal biostimulation with no granuloma formation. • Indicates feasibility of low-viscosity PCL/CMC for precise intradermal regenerative therapy. There is a gradual shift towards injecting diluted injectable collagen biostimulators (ICBs) into the dermis to achieve a smaller drug dosage but stronger stimulation of collagen regeneration. However, the safety and efficacy of this approach remain uncertain. The morphological characteristics of original and diluted polycaprolactone/carboxymethyl cellulose (PCL/CMC) gel with/without lidocaine were examined using scanning electron microscopy. Rheological behavior was evaluated with a rheometer. Original or diluted PCL/CMC gel was injected into the dorsal skin of 12 New Zealand white rabbits at intradermal (ID) and subcutaneous (SC) layers. After 3 and 9 months, injection site skin was analyzed by pathological and immunofluorescence staining. Microspherical PCL showed significant hydrolysis after dilution and fully disintegrated at 1:5 dilution. Rheology revealed decreased elastic modulus in diluted PCL/CMC gel. No adverse reactions such as granuloma were observed. Both SC and ID injections significantly promoted collagen and elastin regeneration. PCL/CMC increased type I and III collagen regardless of administration route; 1:5 diluted PCL/CMC induced higher type I collagen. Additionally, only ID-injected 1:5 diluted PCL/CMC increased type XVII collagen. Diluted PCL/CMC gel matches rheological requirements for intradermal injection and might promote collagen and elastic fiber regeneration more effectively than subcutaneous injection.