Local delivery of pirfenidone by PLA implants modifies foreign body reaction and prevents fibrosis

Alexey Fayzullin; Semyon Churbanov; Natalia Ignatieva; Olga Zakharkina; Mark Tokarev; Daniil Mudryak; Yana Khristidis; Maxim Balyasin; Alexandr Kurkov; Elena N. Golubeva; Nadezhda A. Aksenova; Tatyana Dyuzheva; Peter Timashev; Anna Guller; Anatoly Shekhter

doi:10.3390/biomedicines9080853

Local delivery of pirfenidone by PLA implants modifies foreign body reaction and prevents fibrosis

Alexey Fayzullin, Semyon Churbanov, Natalia Ignatieva, Olga Zakharkina, Mark Tokarev, Daniil Mudryak, Yana Khristidis, Maxim Balyasin, Alexandr Kurkov, Elena N. Golubeva, Nadezhda A. Aksenova, Tatyana Dyuzheva, Peter Timashev, Anna Guller, Anatoly Shekhter

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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.

Original language	English
Article number	853
Pages (from-to)	1-33
Number of pages	33
Journal	Biomedicines
Volume	9
Issue number	8
DOIs	https://doi.org/10.3390/biomedicines9080853
Publication status	Published - 21 Jul 2021

Bibliographical note

Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

implantable drug delivery systems
pirfenidone
polylactic acid
polymer implants
foreign body reaction
fibrosis
peri-implant fibrosis
anti-fibrotic therapy
quantitative histopathology
collagen

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10.3390/biomedicines9080853Licence: CC BY

Publisher version (open access)Final published version, 1.98 MBLicence: CC BY

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Fayzullin, A., Churbanov, S., Ignatieva, N., Zakharkina, O., Tokarev, M., Mudryak, D., Khristidis, Y., Balyasin, M., Kurkov, A., Golubeva, E. N., Aksenova, N. A., Dyuzheva, T., Timashev, P., Guller, A., & Shekhter, A. (2021). Local delivery of pirfenidone by PLA implants modifies foreign body reaction and prevents fibrosis. Biomedicines, 9(8), 1-33. Article 853. https://doi.org/10.3390/biomedicines9080853

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title = "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 (\textasciitilde{}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.",

keywords = "implantable drug delivery systems, pirfenidone, polylactic acid, polymer implants, foreign body reaction, fibrosis, peri-implant fibrosis, anti-fibrotic therapy, quantitative histopathology, collagen",

author = "Alexey Fayzullin and Semyon Churbanov and Natalia Ignatieva and Olga Zakharkina and Mark Tokarev and Daniil Mudryak and Yana Khristidis and Maxim Balyasin and Alexandr Kurkov and Golubeva, \{Elena N.\} and Aksenova, \{Nadezhda A.\} and Tatyana Dyuzheva and Peter Timashev and Anna Guller and Anatoly Shekhter",

note = "Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2021",

month = jul,

day = "21",

doi = "10.3390/biomedicines9080853",

language = "English",

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Fayzullin, A, Churbanov, S, Ignatieva, N, Zakharkina, O, Tokarev, M, Mudryak, D, Khristidis, Y, Balyasin, M, Kurkov, A, Golubeva, EN, Aksenova, NA, Dyuzheva, T, Timashev, P, Guller, A & Shekhter, A 2021, 'Local delivery of pirfenidone by PLA implants modifies foreign body reaction and prevents fibrosis', Biomedicines, vol. 9, no. 8, 853, pp. 1-33. https://doi.org/10.3390/biomedicines9080853

TY - JOUR

T1 - Local delivery of pirfenidone by PLA implants modifies foreign body reaction and prevents fibrosis

AU - Fayzullin, Alexey

AU - Churbanov, Semyon

AU - Ignatieva, Natalia

AU - Zakharkina, Olga

AU - Tokarev, Mark

AU - Mudryak, Daniil

AU - Khristidis, Yana

AU - Balyasin, Maxim

AU - Kurkov, Alexandr

AU - Golubeva, Elena N.

AU - Aksenova, Nadezhda A.

AU - Dyuzheva, Tatyana

AU - Timashev, Peter

AU - Guller, Anna

AU - Shekhter, Anatoly

N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2021/7/21

Y1 - 2021/7/21

N2 - 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.

AB - 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.

KW - implantable drug delivery systems

KW - pirfenidone

KW - polylactic acid

KW - polymer implants

KW - foreign body reaction

KW - fibrosis

KW - peri-implant fibrosis

KW - anti-fibrotic therapy

KW - quantitative histopathology

KW - collagen

UR - https://www.mdpi.com/2227-9059/9/8/853

UR - https://www.scopus.com/pages/publications/85111701526

U2 - 10.3390/biomedicines9080853

DO - 10.3390/biomedicines9080853

M3 - Article

C2 - 34440057

SN - 2227-9059

VL - 9

SP - 1

EP - 33

JO - Biomedicines

JF - Biomedicines

IS - 8

M1 - 853

ER -

Local delivery of pirfenidone by PLA implants modifies foreign body reaction and prevents fibrosis

Abstract

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Keywords

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