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Stocco, Elena (2015) Tailored PVA/ECM scaffolds for focal articular cartilage defects. [Ph.D. thesis]

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Abstract (english)

Focal chondral defects impair considerably patients’ quality of life and may predispose for osteoarthritis. The strong association between age and increasing incidence of osteoarthritis marks it as an age related disease. However, osteoarthritis can be also consequence of other concomitant disorders; among these, the hereditary disease haemophilia stands out. The articular problems of patients with haemophilia begin still in infancy, when minor injuries result in recurrent hemarthroses that may predispose for haemophilic arthropathy. The lack of efficient modalities of treatment has prompted research into tissue engineering, whose basic approach depends upon the interaction between cells, scaffolds and signalling factors to create in vitro a biological tissue construct to implant in vivo, mimicking the tissue of interest. Engineering cartilage is no exception to this approach. Such tissue engineering strategies are still adopted in orthopaedic surgical practice, providing for autologous chondrocytes implants with or without a supporting matrix in order to promote cartilage regeneration. Conversely, in patients with haemophilia, current available strategy can only slow the progression of joint damage, without recovery of tissue integrity.
The aim of this work was twofold. At first, a novel supporting structure to treat focal articular defects was manufactured and characterized. Then, the feasibility of using haemophilic chondrocytes for autologous cartilage tissue engineering was considered.
By a controlled chemical oxidation, 1% or 2% hydroxyls of the synthetic polymer polyvinyl alcohol (PVA) backbone were oxidized to carbonyls. Oxidation was verified by 2,4-dinitrophenylhydrazine assay and covalent binding with lysozyme. After physical cross-linking of polymeric solutions, 1% and 2% oxidized PVA scaffolds were evaluated and compared to neat PVA scaffolds. Scanning Electron Microscopy (SEM) micrographs showed oxidation to affect hydrogel surface continuity. Moreover, increasing carbonyls content, physical and biodegradation properties were modulated. In particular, mechanical properties, hydrodynamic radius of particles, thermal characteristics, and crystallinity degree of PVA hydrogels decreased with oxidation rate. Conversely, swelling behavior and protein release were enhanced, suggesting oxidized PVA potentiality as protein delivery system. Most important, biocompatibility and biodegradability of PVA scaffolds increased along with oxidation. After 12-week in vivo implantation, hydrogels did not elicit severe inflammatory reactions. Nevertheless, a little limphomonocytic infiltration by CD3+ and F4/80+ cells suggested a role for inflammatory populations in implant reabsorption.
Afterwards, non-haemophilic and haemophilic chondrocytes were isolated and cultured. After a morphological evaluation through optical microscopy, cells were compared for the expression of specific mRNAs (COL2A1, COL9A3, COMP; ACAN; SOX9) by RT-PCR and specific surface markers (CD44; CD49c; CD49e; CD49f; CD151; CD26; CD73) by flow cytometry. RT-PCR results confirmed the expression of target genes and any immunophenotypic difference was observed despite haemophilic chondrocytes were exposed to blood in vivo which is one of the major responsible of cytotoxicity. Flow-cytometry showed that both subcultures consisted of CD44+/CD49c+/CD49e+/CD151+/CD73+/CD49f-/CD26- cells. High expression of adhesion molecules (e.g. CD44, CD49c, CD49e) involved in cell-cell or cell-matrix interactions, revealed high chondrogenic capacity. As it is well known PVA inability in sustaining cell adhesion, a bio-hybrid composite scaffold was than obtained combining the biomechanical properties of 1% oxidized PVA with an alternative matrix source that is decellularized Wharton’s jelly (W’s J). The hydrogel itself and the more specific decellularized articular cartilage (AC) matrix, combined with 1% oxidized PVA, were used as controls. Both cell populations behaviour was evaluated after seeding cells on scaffolds. According to SEM micrographs and Thiazolyl Blue Tetrazolium Blue proliferation assay, W’s J matrix showed a singular attitude in sustaining adhesion and proliferation of both cell populations.
Our results highlighted oxidized PVA as a smart biomaterial useful for manufacturing scaffolds with customizable mechanical behaviour, protein-loading ability and biodegradability. Moreover, this study contributes to the definition of haemophilic chondrocytes phenotype, providing new potential markers to characterize them. Our preliminary evidences support the chance of using haemophilic chondrocytes for autologous implant in haemophilic patients. W’s J/oxidized 1% PVA may be considered as an innovative and easily available scaffold for cartilage restoration both in haemophilic and non-haemophilic patients.

Abstract (italian)

I difetti condrali focali compromettono significativamente la qualità della vita dei pazienti predisponendo all'osteoartrite. Eziologicamente sussiste una forte associazione tra l'età del paziente e l’incidenza di osteoartrite, consentendo di identificarla come una malattia legata all’invecchiamento. L’osteoartrite tuttavia può essere anche conseguenza di patologie concomitanti; tra queste l’emofilia, coagulopatia ereditaria. I problemi articolari nei pazienti emofilici esordiscono già nell’infanzia, quando danni minori possono esitare in emartri ricorrenti predisponendo all’artropatia emofilica.
L’assenza di trattamenti soddisfacenti per efficacia ha spinto la ricerca nell’ambito dell’ingegneria tissutale, il cui approccio di base si fonda sull’interazione tra cellule, scaffolds e fattori di crescita. L’obiettivo è di creare in vitro costrutti biologici funzionali, capaci di mimare il tessuto d’interesse dopo impianto.
Alcune strategie di ingegneria tissutale sono già adottate in chirurgia ortopedica. Esse prevedono l’impianto di condrociti autologhi come tali o supportati da matrici al fine di promuovere la rigenerazione e quindi l’integrità del tessuto compromesso. Di esse tuttavia i pazienti emofilici non possono beneficiare, disponendo ad oggi di approcci volti a rallentare solamente la progressione del danno senza favorirne il recupero.
Lo scopo di questo lavoro di Tesi è stato duplice. Dapprima è stato realizzato e caratterizzato un nuovo scaffold funzionale al recupero del danno cartilagineo focale. Successivamente, è stata valutata la possibilità di utilizzare i condrociti del paziente emofilico nella prospettiva di un impianto autologo.
Mediante una reazione chimica di ossidazione, l’1% o il 2% dei gruppi ossidrilici presenti sul backbone del polimero sintetico polyvinyl alcohol (PVA) sono stati ossidati a gruppi carbonilici. L’avvenuta ossidazione è stata verificata mediante saggio con 2,4-dinitrofenilidrazina e binding covalente di lisozima. A seguito di cross-linking fisico delle soluzioni polimeriche, scaffolds in PVA ossidato all’1% ed al 2% sono stati quindi valutati e confrontati con scaffolds in PVA non ossidato.
La microscopia elettronica a scansione ha rivelato come l’impiego di soluzioni polimeriche ossidate influenzi la continuità superficiale degli idrogeli risultanti. Inoltre, aumentando il contenuto in carbonili, anche le proprietà fisiche e di biodegradazione risultano modulate. In particolare, la meccanicità degli scaffolds, il raggio idrodinamico delle particelle, le proprietà termiche ed il grado di cristallinità degli idrogeli di PVA diminuiscono all’aumentare del grado di ossidazione. Diversamente, il rigonfiamento ed il rilascio proteico aumentano, suggerendo potenzialità di protein-delivery system. Anche le caratteristiche di biocompatibilità e biodegradazione sono state considerate. Dopo 12 settimane di impianto sottocutaneo in vivo, gli idrogeli non hanno provocato gravi reazioni infiammatorie. Tuttavia, una limitata infiltrazione linfomonocitaria da parte di cellule CD3+ e F4/80+ ha suggerito un ruolo delle popolazioni infiammatorie nel riassorbimento dell’impianto: all’aumento del grado di ossidazione è stato riscontrato un incremento del tasso di degradazione degli scaffolds.
I condrociti da paziente emofilico e non emofilico sono stati quindi isolati e messi in coltura. Dopo valutazione morfologica mediante microscopia ottica, le cellule sono state comparate per l’espressione di specifici mRNA (COL2A1; COL9A3; COMP; ACAN; SOX9) attraverso RT-PCR; e per l’espressione di marker di superficie caratteristici (CD44; CD49c; CD49e; CD49f; CD151; CD26; CD73) attraverso analisi di citofluorimetria. I risultati di RT-PCR hanno confermato l’espressione dei geni target; inoltre differenze immunofenotipiche non sono state osservate tra i tipi cellulari sebbene i condrociti da paziente emofilico fossero stati esposti in vivo al sangue, tra i maggiori responsabili di citotossicità. La citofluorimetria ha mostrato dunque che entrambe le popolazioni presentavano cellule con immunofenotipo CD44+/CD49c+/CD49e+/CD151+/CD73+/CD49f-/CD26-. L’elevata espressione di molecole di adesione (e.g. CD44, CD49c, CD49e) coinvolte in interazioni cellula-cellula o cellula-matrice, ha suggerito un alto potenziale condrogenico.
Essendo nota l’inadeguatezza del PVA nel promuovere l’adesione cellulare, è stato realizzato uno scaffold bio-ibrido composito combinando le proprietà meccaniche del PVA ossidato all’1% con una matrice extracellulare decellularizzata non tessuto specifica: la gelatina di Wharton. L’idrogel tal quale e la più specifica matrice da cartilagine articolare decellularizzata, combinata con il PVA ossidato all’1%, sono stati usati come controllo.
Il comportamento di entrambe le popolazioni cellulari è stata valutata dopo semina sugli scaffolds. Immagini di microscopia elettronica a scansione ed il saggio di proliferazione con Thiazolyl Blue Tetrazolium Blue hanno mostrato come la matrice da W’s J sostenga in modo singolare l’adesione e la proliferazione di entrambe le popolazioni cellulari.
I risultati di questo lavoro di Tesi hanno consentito di identificare nel PVA ossidato un biomateriale intelligente per la realizzazione di scaffolds con proprietà meccaniche, di protein-loading, e di biodegradazione modulabili. Inoltre, questo studio ha contribuito a definire il fenotipo dei condrociti da paziente emofilico, provvedendo a fornire nuovi potenziali marker per caratterizzarli e suggerendo la possibilità di impianto autologo. Lo scaffold composito W’J/ PVA ossidato 1% potrebbe infine essere considerato come una struttura innovativa per il recupero del danno cartilagineo sia in pazienti affetti da osteoartrite idiopatica che secondaria.

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EPrint type:Ph.D. thesis
Tutor:Grandi, Claudio
Ph.D. course:Ciclo 27 > scuole 27 > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE
Data di deposito della tesi:30 January 2015
Anno di Pubblicazione:30 January 2015
Key Words:Polyvinyl alcohol, articular cartilage defects, chondrocytes, osteoarthritis, haemophilic arthropathy. Polivinil alcol, difetti cartilaginei, condrociti, osteoartrite, artropatia emofilica
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Area 03 - Scienze chimiche > CHIM/06 Chimica organica
Area 05 - Scienze biologiche > BIO/16 Anatomia umana
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:7842
Depositato il:10 Nov 2015 11:20
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