Local Delivery of Pirfenidone by PLA Implants Modifies Foreign Body Reaction and Prevents Fibrosis

Abstract

Peri-implant fibrosis (PIF) increases the postsurgical risks after implantation and limits the efficacy of the implantable drug delivery systems (IDDS). Pirfenidone (PF) is an oral anti-fibrotic drug with a short (<3 h) circulation half-life and strong adverse side effects. In the current study, disk-shaped IDDS prototype combining polylactic acid (PLA) and PF, PLA@PF, with prolonged (~3 days) PF release (in vitro) was prepared. The effects of the PLA@PF implants on PIF were examined in the rabbit ear skin pocket model on postoperative days (POD) 30 and 60. Matching blank PLA implants (PLA0) and PLA0 with an equivalent single-dose PF injection performed on POD0 (PLA0+injPF) served as control. On POD30, the intergroup differences were observed in α-SMA, iNOS and arginase-1 expressions in PLA@PF and PLA0+injPF groups vs. PLA0. On POD60, PIF was significantly reduced in PLA@PF group. The peri-implant tissue thickness decreased (532 ± 98 µm vs. >1100 µm in control groups) approaching the intact derma thickness value (302 ± 15 µm). In PLA@PF group, the implant biodegradation developed faster, while arginase-1 expression was suppressed in comparison with other groups. This study proves the feasibility of the local control of fibrotic response on implants via modulation of foreign body reaction with slowly biodegradable PF-loaded IDDS.

A defined road to tracheal reconstruction: laser structuring and cell support for rapid clinic translation

“…Macrophages and giant multinuclear cells of foreign bodies are the most important regulatory cells defining the direction of the host immune response. It was shown that they expressed markers of their functional state [ 23 ]. The control over macrophages using pharmaceuticals can allow the regulation of the resorption period and the intensity of tissue infiltration with immune cells through manipulating cell homing signals.…”

“…The distribution of animals into groups is shown in Table 2 . Before the surgery, the animals were anesthetized by intramuscular injection of zoletil and xylazine as described elsewhere [ 22 , 23 ]. The material was fixed in a tracheal defect in male rabbits at the age of 4–6 months (weight of 3.5–5 kg).…”

Implantable Drug Delivery Systems and Foreign Body Reaction: Traversing the Current Clinical Landscape

“…Possibly, other drugs able to control local tissue proliferation at the implantation site (for various types of IDDSs and their anatomical locations) may enter the scene. Our own recent studies have demonstrated a possibility of re-purposing pirfenidone for FBR-controlling IDDS [ 129 ]. Taken together, these trends may indicate a future direction of exploration and whether these features can be reconstructed for the implants placed in other tissues.…”

Failure Analysis of TEVG’s II: Late Failure and Entering the Regeneration Pathway

“…Chemical modifications include coatings with slow-releasing antifibrotic drugs, such as halofuginone, pirfenidodone and matisinib, inhibiting the collagen synthesis and myofi- To avoid the formation of a fibrotic capsule or a fibrotic thrombus, chemical and physical modifications of the biomaterials have been proposed on different biomaterials. Chemical modifications include coatings with slow-releasing antifibrotic drugs, such as halofuginone, pirfenidodone and matisinib, inhibiting the collagen synthesis and myofibroblasts activation [42,43]. Likewise, other authors have also included the use of interference RNAs for Rapamycin and Col1 [44].…”