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Grandi, Francesca (2017) Short bowel syndrome in etĂ  pediatrica: dall'eziopatogenesi al trattamento. [Ph.D. thesis]

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Abstract (english)

Short Bowel Syndrome (SBS) in children is a condition of intestinal malabsorption and dysmotility, caused by rare congenital malformations or acquired diseases, requiring extensive bowel surgical resection which in severe cases can lead to irreversible intestinal failure.
Nowadays, the management of pediatric patients affected by SBS is multidisciplinary, involving different possible strategies of treatment: total parenteral nutrition, surgical intestinal lengthening up to intestinal transplantation. The main aim of all these approaches is to promote bowel absorption, but none of them is free from complications that may impair children quality of life.
Based on these considerations, this Research Project aims to identify new options to manage and treat SBS. Hence, two aspects were considered: a clinical and an experimental one.
As known, the management of SBS patients requires a careful follow-up by a multispecialistic team, able to survey their possible short- and long-term complications and their progressive weaning from parenteral support. Considered this, the clinical part of this Research Project focused on the evaluation of citrulline as a reliable serum marker of residual bowel function. The goal was to verify the possibility of suggesting it for routine dosage in case of intestinal failure, similarly to creatinine in renal impairment and for transaminases in hepatic failure.
Briefly, we identified a sample population consisting of 10 SBS patients, age ≤ 5 years and residual bowel length (after surgery) ≤ 100 cm. Patients followed-up with parenteral and enteral nutrition programs and were subjected to citrulline dosages at least 6 weeks after surgery.
At the end of the clinical evaluation, we highlighted that serum values of citrulline are strongly related with both the residual intestinal length and the duration of their dependence on parenteral support (p < 0.01).
Likewise, the experimental research turned its attention to Tissue Engineering that is a new medical science which aims to achieve functionally active tissue substitutes by scaffolds, cells and growth factors.
The second part of the Research Project focused on the possibility to develop a bio-synthetic scaffold for tissue engineering applications in SBS. We manufactured, according to a protocol we patented, new hydrogels based on polyvinyl alcohol with a degree of oxidation of 1% and 2% respectively. The purpose of the chemical oxidation was to confer to the derived biomaterial a certain biodegradation rate. Hence, oxidized hydrogels obtained via physical cross-linking (freezing-thawing) were compared to native PVA hydrogels for their morpho-mechanical and biological properties by means of ultrastructural analysis with scanning electron microscopy, tensile tests, swelling index analysis, and in vivo biodegradation studies. These investigations showed that the strength and the stiffness of the polymer are significantly related to the chemical modification as they decrease along with the oxidation degree; conversely, the swelling and the biodegradation rate increase along with it.
The obtained results led us to identify in scaffolds prepared by using 1% Oxidized PVA the supports with the most adequate morpho-mechanical and biodegradation properties to our purposes. Hereafter, it was set up a composite scaffold in 1% Oxidized PVA cross-linked with decellularized intestinal extracellular matrix (ECM). The combination of the polymer with the bioactive matrix allowed us to obtain a support with good mechanical properties and able to promote cell growth and proliferation.
Briefly, the small intestine of adult rats was removed and decellularized according to the detergent-enzymatic protocol by Meezan. After having assessed the effectiveness of the procedure (DAPI staining) the acellular matrix was characterized by histological staining (hemotoxylin/eosin). Thereafter, the extracellular matrix (intact and homogenized) was crosslinked with 1% Oxidized PVA and the ability of the composite scaffold to support cell adhesion and proliferation was investigated using a primary culture of adipose mesenchymal stem cells. After 7 days from seeding, a significant cell growth on the composite scaffolds was observed in comparison with the nude polymeric support. Finally, based on of the TESI (Small Intestine Tissue Engineering) model, the scaffold was implanted in the omentum of adult rats; after 4-weeks, composite scaffolds demonstrated their ability to induce the formation of a composite pseudoepithelial tissue with intestinal-like features.

Abstract (italian)

La sindrome dell'intestino corto o Short Bowel Syndrome (SBS) in età pediatrica è una condizione di malassorbimento e dismotilità intestinali, conseguenza di rare malformazioni congenite o patologie acquisite, che comportino resezioni chirurgiche più o meno estese dell'intestino sino, nei casi più gravi, ad insufficienza intestinale.
Allo stato attuale, la gestione dei pazienti affetti da SBS è multidisciplinare; varie le possibili strategie terapeutiche: la nutrizione parenterale totale, la chirurgia di "allungamento intestinale" e, nelle fasi più avanzate della patologia, il trapianto di intestino. L'obiettivo primario di tutti questi approcci è quello di promuovere l'assorbimento intestinale, tuttavia nessuno di essi è scevro da complicanze capaci di inficiare la qualità della vita dei pazienti.
Sulla base delle precedenti considerazioni, questo Progetto di Ricerca si propone di identificare nuovi approcci per il management ed il trattamento della SBS. A tal fine, la ricerca si è sviluppata su due versanti: uno clinico e l’altro sperimentale.
Come noto, la gestione della SBS necessita di un attento follow-up dei pazienti da parte di un'equipe multispecialistica che sia in grado di monitorare, nel breve e nel lungo termine, le possibili complicanze nonché la svezzabilità del paziente dal supporto parenterale. In tale senso, nella parte di ricerca clinica è stata studiata e valutata l'attendibilità della citrullina come marker sierico della funzionalità intestinale residua; l’obiettivo è di proporne un impiego routinario esattamente come avviene per la creatinina nell'insufficienza renale e per le transaminasi nell'insufficienza epatica.
A tale scopo, all’interno del nostro campione di pazienti affetti da SBS e seguiti in follow-up, è stata individuata una sottopopolazione campionaria costituita da 10 pazienti inseriti in un programma di nutrizione parenterale ed enterale domiciliare, con età ≤ 5 anni e lunghezza intestinale residua (dopo chirurgia) ≤ 100 cm, che sono stati sottoposti a dosaggio della citrullinemia ad almeno 6 settimane di distanza dalla chirurgia.
I valori della citrullinemia sierica sono risultati essere correlati in maniera statisticamente significativa (p < 0,01) sia con la lunghezza intestinale residua di tali pazienti, che con la durata della loro dipendenza dal supporto parenterale.
In parallelo, la Ricerca Sperimentale ha rivolto l’attenzione verso una nuova disciplina medica: l’Ingegneria Tissutale. Quest’ultima è una scienza multidisciplinare che si propone di realizzare in laboratorio sostituti tissutali funzionalmente attivi attraverso l’impiego di scaffold, cellule e fattori di crescita. In particolare, in questa seconda parte del progetto di ricerca è stata investigata la possibilità di sviluppare uno scaffold bio-sintetico per applicazioni di ingegneria tissutale intestinale. Brevemente, sono stati realizzati, secondo un protocollo brevettato dal nostro gruppo di ricerca, dei nuovi idrogeli a base di polivinil alcol con un grado di ossidazione dell’1% e del 2%. L'obiettivo dell’ossidazione chimica è stato quello di conferire al biomateriale caratteristiche di biodegradabilità in confronto alla sua forma non ossidata. Dopo cross-linking fisico mediante freezing-thawing, idrogeli in PVA nativo e PVA ossidato sono stati caratterizzati per le loro proprietà morfo-meccaniche e biologiche, tramite analisi ultrastrutturali di microscopia elettronica a scansione, test di trazione, valutazione dell’indice di rigonfiamento e studio di biodegradazione in vivo. Queste indagini hanno dimostrato che la resistenza meccanica e la rigidità del polimero vengono modulate dalla modifica chimica, diminuendo all’aumentare del grado di ossidazione. Diversamente, l’indice di rigonfiamento e il tasso di biodegradazione sono tanto più elevati quanto più aumenta la percentuale dei gruppi carbonilici derivati dall’ossidazione. I risultati ottenuti hanno consentito di identificare nel PVA ossidato all’1% il polimero con caratteristiche morfo-meccaniche e di biodegradazione congeniali ai nostri scopi. Sulla base di questo, è stato allestito uno scaffold composito, costituito da PVA ossidato all’1% cross-linkato con matrice extracellulare intestinale decellularizzata (intera e omogenizzata): la combinazione del polimero (avente proprietà meccaniche e di biocompatibilità/biodegradazione ottimali) con la matrice bioattiva ha consentito di ottenere un supporto capace di favorire la crescita e la proliferazione cellulare. Brevemente, la realizzazione dello scaffold composito ha previsto l'espianto di intestino tenue da ratto adulto e la successiva decellularizzazione del tessuto con metodo detergente-enzimatico secondo Meezan. Dopo aver valutato l'efficacia della procedura di decellularizzazione (marcatura con DAPI) la matrice acellulare è stata caratterizzata tramite colorazione con ematossilina/eosina. A seguito del cross-linking della matrice extracellulare (intera e liofilizzata) con l’idrogelo in PVA ossidato all’1%, la capacità dello scaffold composito nel sostenere l'adesione e la proliferazione cellulare è stata indagata utilizzando cellule staminali mesenchimali da tessuto adiposo umano. A 7 gg dalla semina è stato possibile riscontrare una crescita cellulare significativa sugli scaffold compositi in confronto al solo supporto polimerico. Infine, sulla scorta del modello TESI (Tissue Engineering Small Intestine), tali scaffold sono stati impiantati in omento di ratti adulti, dimostrando, ad un end-point di 4 settimane, la capacità di generare uno pseudoepitelio composito con caratteristiche di tipo intestinale.

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EPrint type:Ph.D. thesis
Tutor:Gamba, Piergiorgio
Ph.D. course:Ciclo 29 > Corsi 29 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE SANITARIA
Data di deposito della tesi:17 January 2017
Anno di Pubblicazione:17 January 2017
Key Words:short bowel syndrome; pediatric; congenital malformations
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/20 Chirurgia pediatrica e infantile
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:9861
Depositato il:03 Nov 2017 11:15
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