Utjecaj BPC 157 na cijeljenje frakture, ektopičnu kost i heterotopnu osifikaciju u štakora [The effect of BPC 157 on fracture healing, ectopical bone and heterotopic ossification in the rat]

Starčević, Neven (2017) Utjecaj BPC 157 na cijeljenje frakture, ektopičnu kost i heterotopnu osifikaciju u štakora [The effect of BPC 157 on fracture healing, ectopical bone and heterotopic ossification in the rat]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

INTRODUCTION Heterotopic ossification denotes bone formation in extraosseus tissues, it is most commonly acquired in nature. It’s development follows extremity injuries, burns or spinal cord injuries and is often linked to a significant functional impairment for the patient. Although it can arise after a multitude of injuries, in our clinical practice it is often the result of fractures about the elbow, where it is functionally of paramount importance. BPC 157 was shown as a potent agent in a myriad of experimental models where complex healing was required to restore function, therefore we think that the research of the effect of BPC 157 is worthwhile. MATERIALS AND METHODS We based our experiment on the model described by Zotz et al. and was performed on Wistar Albino male rats, kept in standard conditions. We modified the aforementioned model by adding a fracture and implanting a fragment of bone into the thigh of the hind leg, this gave us two models for which the design of the study is identical. BPC 157 was administered as a 99% pure solution in drinking water and applied in two dosages 10μg/kg and 10ng/kg administered per orally. The study was conducted as co-treatment and post-treatment, to each group we randomly assigned 5 animals in co-treatment and 6 in post-treatment, 96 animals per model, 192 animals in total. The animals were euthanized on the 7th, 14th, 21st and 28th day in co-treatment and 42nd and 56th day in post-treatment, on the same day functional measurements were carried out, which included measurement of contracture of the operated leg, extensor postural test (EPT), gait analysis, motor function index (MFI). After euthanasia, specimens were collected and classical radiography and histological analysis were performed. Statistical analysis was performed and significance was set at p < 0,05. RESULTS The experimental groups showed better fracture healing in the co-treatment, and better nonunion healing in the post-treatment group, ectopic bone resorption was enhanced, functional impairment lessened and statistical analysis showed significance at p < 0,05. The aforementioned effects were more pronounced in the 10μg/kg dose, although the 10ng/kg dose showed clinically significant improvement. We could not replicate the results of Zotz et al. and achieve development of heterotopic ossification. CONCLUSION BPC 157 enhances fracture and nonunion healing, helps to preserve functional integrity of the hind leg postoperatively and helps with ectopic bone resorption.

Abstract in Croatian

UVOD Heterotopna osifikacija (HO) je pojam koji označava stvaranje kosti u nekoštanom tkivu, najčešće je stečeno stanje povezano s ozljedama ekstremiteta, opeklinama ili ozljedom kralješničke moždine te često predstavlja znatno funkcionalno ograničenje za pacijenta. Iako se može javiti nakon bilo koje ozljede, u našoj kliničkoj praksi je klinički značajna HO povezana s frakturama u području lakta, gdje često bitno utječe na funkcionalni status. BPC 157 se dosada pokazao kao moćan agens u liječenju različitih kompleksnih ozljeda i narušenja funkcijskog intergriteta na brojnim modelima, stoga smatramo da je istraživanje učinka na heterotopnu osifikaciju i konkomitantu frakturu vrijedno pažnje. MATERIJALI I METODE Naše istraživanje smo temeljili na literaturnom modelu autora Zotz. i sur., te smo ga proveli na mužjacima Wistar Albino štakora držanim u standardnim uvjetima. Taj model smo modificirali dodavanjem frakture te implantacijom kortikospongioznog cilindra u mišić natkoljenice te tako dobili dva eksperimentalna modela, za koje je dizajn studije istovjetan. BPC 157 je primjenjivan kao 99% čist pripravak, otopljen u vodi za piće korišten je u dozama 10μg/kg i 10ng/kg administriran peroralno. Pokus je proveden kao kotretman i posttretman te je svakoj skupini dodijeljeno randomizacijom 5 štakora u kotretmanu te 6 u posttretmanu (ukupno 96 životinja po modelu, 192 životinje za cijeli pokus). Žrtvovanja su provođena 7.,14., 21. i 28. dan postoperativno u kotretmanu a 42. i 56. dana postoperativno u posttretmanu. Navedenih dana su se vršila i funkcionalna ispitivanja koja su obuhvaćala opažanje kontrakture operirane noge, mjerenje pritisne sile (EPT), analizu hoda, test motorne funkcije (MFI). Nakon žrtvovanja su pripremljeni preparati koji su podvrgnuti RTG snimanju te histološkoj obradi. Svi rezultati su podvrgnuti statističkoj obradi, a značajnost je postavljena kada p < o,o5. REZULTATI Za eksperimentalne skupine je pokazano poboljšano cijeljenje frakture u kotretmanu i frakture koja otežano cijeli u posttretmanu, poboljšana resorpcija ektopične kosti u modificiranom modelu, očuvanje funkcije stražnje noge u oba modela, svi navedeni rezultati su se pokazali kao statistički značajni pri p < 0,05. Opažen je jači učinak BPC 157 u dozi 10μg/kg , no i doza 10ng/kg pokazuje klinički značajan učinak. Nismo uspjeli reproducirati rezultate Zotz i sur. te izazvati stvaranje HO. ZAKLJUČAK BPC 157 pomaže u cijeljenju frakture i frakture koja otežano cijeli, pomaže u očuvanju funkcionalnog integriteta stražnje noge nakon operacijskog zahvata te pomaže u resorpciji ektopične kosti.

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