« Biomaterials for Osteoarticular and Dental Ageing »

INSERM UMR_S 791

LIOAD, Centre for osteoarticular and dental tissue engineering [email protected] Skeleton cooperative institute School of dental surgery and university hospital Nantes, France

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NANTES | FRANCE www.congres-nantes.fr

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Welcome to Nantes Share moments of exception…

France, 1st business touristic destination worldwide

Nantes,

The first European city you fly over when you’re flying from New York to Paris or Berlin

+

Nantes,

Western France’s capital

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« BIOREGOS » Biomaterial and osteoarticular regeneration Network

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Chemistry

Nano technology Bone characterization

Biomaterials, Chemistry Cell biology Stem cells

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Biology

• LIOAD, UMR_S 791, Nantes University / INSERM : (Pierre Weiss, Jérome Guicheux) • Biomaterials, stem cells , Bone and cartilage tissue engineering,.periodontal and dental tissues.

• UPRES EA 3826, Nantes University – (Gilles Amador)

• Infected bone and local treatment

• CRIP, National Veterinary School of Nantes / ONIRIS – (Olivier Gauthier)

• Animal surgery facilities animal models.

• Team « Marine Polysaccharides » Biotechnology and Marine Molecules laboratory , Nantes IFREMER (Sylvia colliec)

– Bioactives marine Polysaccharides, GAGs like.

• MINT, UMR_S 1066, Angers University : – (JP Benoit, Franck Boury)

• Nano medicine and nano particles. Drug delivery.

• GEROM UPRES EA 4658 Angers University : – (Daniel Chappard)

• Malign and benign Osteopathy, Bone remodeling, micro architecture, Bone quality. U791

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New materials and Caracterization •

IMN, UMR 6502, Nantes University / CNRS – Material, Ionic liquids, Carbon and silica nano tubes and fibers – Mechanical properties (LGMPA)

• CEISAM, UMR 6230, Nantes University / CNRS – Organic and mineral chemistry.

•

GEM, UMR 6183, Central school of Nantes, Nantes University / CNRS – Mathematical modelisation of soft materials

•

IRCCyN, UMR 6597, Nantes University /. CNRS – Medical imaging

•

FR 2575 (LPEC UMR 6087- PCI UMR 6120-) Le Mans University / CNRS – Materials, Rheology, nanotechnologies, chemistry

•

Associated team: – CRT : CTTM, Le Mans • Technology transfer unit for medical use

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Bone fragility UMR_S 922

Phosphate sensing U791

SC3M SCIAM

Experimental radiology animal platform

CRIP

LIOAD, U791, UN IMN, UMR 6502, UN MINTU646, UA GEM, UMR 6183 ,ECN PCI, UMR 6120, UM

Stem cells (MSC, IPS)

LIOAD, U791, UN IMN, UMR 6502, UN CEISAM, UMR 6230, UN UMRS 922, UA UPRES EA 3826, UN UMR 6087 LPEC IRCCyN, UMR 6597, UN Subatech (prévu)

GRAFTYS

BIOMATLANTE

Articular Cartilage IVD Irradiated bone Hypotrophic bone Infected Osteoporotic Bone

CTTM

SURFACTIS

New clinical ways of characterization 2D ->3D

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SME from our Laboratoires •

Biomatlante 15 Years, Vigneux de Bretagne – – – –

•

50 peoples Collaborations : LIOAD, CTTM, ONIRIS, Nantes Hospital EU 7 : REBORNE, GAMBA Focus: Calcium phosphate ceramics, IBS, membranes…

Graftys 6 Years, Aix en Provence (South of France) – R&D in Nantes

– – – –

•

25 peoples Collaborations : LIOAD, CEISAM, IMN, ONIRIS, EA 3826 ANR : Miadros, BRB, Whatbone, Chondrograft Focus: Osteoporoses, Calcium phosphate cement and BP

Surfactis 7 years, Angers – – – –

3 peoples Collaborations : IVP, U922, LPEC, LIOAD ANR : Calcomed Focus: Functionalization of calcium carbonates, of titane

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A1 : Phosphate/calcium and skeletal cells Calcified tissues

CaP biomaterials

Degradation/resorption

Remodeling/resorption Release

Ca + Pi

Transcription Wild-type MGP Fold change

Mineralisation

fra-1Δ/Δ

Control

KO mice

signaling

Pi

P-ERK1/2

3

* 2

ERK1/2

1 0

Pi (mM)

1

10

1

10

Squelettic cells

Pi [mM]

1

10

Magne 10et al. J Bone Miner Res 2003, Suzuki et al. J Bone Miner Res 2006, Julien et al. Endocrinology 2007, Julien et al. J Bone Miner Res 2009 U791

Injectable bone substitutes

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Physical presentations of IBS What is the scaffold?

Cl I : Granules Suspensions a)Non hardening b)Hardening

Cl II : cement a)Classical CPC +/- resorbable b)macro porous U791

Cl I-a : Non-hardening suspension of 40-80 µm BCP granules in HPMC water solution shown bone ingrowth inside the implant 3 weeks after implantation

Cl II-a Calcium Phosphate Cement (CPC) image of the interface between cement and newly-formed bone 3 weeks after implantation.

Cl I-b : Hardening suspension of ceramics (MBCP®) in resorbable mineral matrix, 6 weeks after implantation (MCPC® Biomatlante, Vigneux de Bretagne, France)

Cl II-b : Porous hardening CPC Matrix, 8 weeks after implantation (I. Khairoun, Graftys HBS®,Graftys SAS, Aix en Provence, France)

Rabbit Model A conic block of macroporous BCP was positioned to close the femoral cavity after injection of the IBS.

A cylindrical defect (6 mm in diameter and 10 mm in length) at the distal femoral end.

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A2: Hard biomaterials :Bone bioactive drug delivery system Healthy Bone

Osteoporotic bone

N

PCa N

chimisorption CaP materials : cement, IBS..

(patent WO03074098) Licence Graftys

Zoledronate

CH2

NaHO 3P

PO3HNa OH

In vivo (OVX)

In vitro Controlled release of TA Reduced bone resorption

120 100 80 60 40 20 0 Contrôle

PCa

*

*

Pca-zolé

Zolé10-6

Josse et al. Adv Mater 2004 et Biomaterials 2005, Guicheux et al. Drug discov today 2005, Grimandi et al. Micros Res Tech 2006, Julien et al. Biomaterials 2007, Faucheux et al J Biomed Mater Res 2009 U791

A2 : Soft biomaterials = Hydrogel

Characterization

Basic Synthesis : HPMC Si

heterogeneous homogeneous

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Nano reinforcement U791

Silated-Hydroxypropylmethylcellulose Matrix (HPMC) + Marines polyssacharides

Marine polysaccharides

Si-HPMC

GY758

+ 10 U791

Compressive modulus (Pa)

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Ionic liquids : homogeneous modification of cellulose R = H, CH3, or CH2-CHOR-CH3 OR

OR

RO

RO

O

O

RO

O RO

RO

OR

OR RO OR

RO

n

heterogeneous

OR

OR

RO

RO

O

O RO

O RO

RO

HO

OR

RO

O

OR RO

O

n Si H3CO

OCH3 OCH3

homogeneous Jean Le BIDEAU, P. Weiss et al., patents U791

Carbon nanotube MWCNTs

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Nano renforcements • • • • •

Micro Calcium carbonate particles Micro calcium phosphate particles Micro fibres of PLA Nano silica fibres Nano silicate particles

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Why Tissue engineering? •2 THERAPEUTIC AXES linked to ageing •Large bone losses. •Articular and IV Cartilage Lesions

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Tissue engineering « The application of the principles and methods of engineering and life sciences toward the development of biological substitutes that restore, maintain or improve tissue function » (Woodfield, 2001).

Biomaterial/scaffold soil

Medium water Cells seeds

Growth factors fertilizer

Magne D, Julien M, Vinatier C, Weiss P, Guicheux J. Bioessays (2005) U791

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Aspiration of bone marrow or fat tissue

CaP

Multiplication 200.106 Cel. (10-12 j)

Implantation of Hybrid graft Cells + Materials

Differentiation Hydrogel 5

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Bone Tissue Engineering • 3 questions ? – What is the best state of MSC differentiation to support bone regeneration into BCP Calcium phosphate ceramics ? – Bone marrow, MSC without differentiation or comitted in bone lineage?

– Are MSC still alive after implantation in animal ? – Are MSC involved in the bone regeneration ?

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Ectopic bone regeneration in nude mice with Biphasic Calcium Phosphate (BCP) and bone marrow stem cells

• Sub-cutaneous implantation of cells and BCP in nude mice after 8 weeks • Evaluation of bone ingrowth by SEM

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Bone regeneration of calvarial defects in Lewis 1a syngenic rat with BCP and bone marrow stem cells • • •

Culture of stem cells on bcp granules in proliferative and osteogenic medium Cellular bridging between granules Extracellular matrix production on the surface of BCP

Day 10

Day 30 U791

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Self-setting network: Silated polymer Network

Dissolution in basic water solution (pH 12.4)

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Integration of cells Si-HPNC viscous phase, pH 7.4 Si-HPMC viscous phase, pH 12.4

Hepes buffer pH 3.6

Cells and culture medium

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A3 : Cartilage and IVD engineering 1- Stem cells from adipose tissue CD 105

Merceron C. et al, Am J Physiol (2010) 2- Large animal model for cartilage tissue engineering

Vinatier C. et al., Curr Stem Cell Res (2009). 3- IVD Fold change

1,2

COL2A1

1 0,8 0,6 0,4 0,2 0

AC AFCNPCNC Clouet J., et al., Drug Discov Today (2009), Clouet J. et al., Rheumatology (2009) 29

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Collaborations ? • • • • • • •

Nano particles toxicity New Hydrogels Stem cell protection and fate MSC / IPS ??? For aged people What about universal cell production ? Bank of stem 4 patents free for licensing

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Thank you

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Paris Univ Hospital, UMR INSERM / U Nantes 791 JM Bouler, J Guicheux, O Gauthier INSERM U747

er UMR CNRS / U Nantes 6230 UMR CNRS / B Bujoli, P Janvier

UPR CNRS 3079 F Fayon, D UPR MassiotCNRS

I Khairoun, Schnitzler UMR V INSERM / U Nantes 791 UMR CNRS / U Nantes 6230 I Khairoun, V Schnitzler JM Bouler, J Guicheux, O Gauthier UMR INSERM / U Nantes 791B Bujoli, P Janvier I Khairoun, V Schnitzler JM Bouler, J Guicheux, O Gauthier

3079

UMR CNRS / U Nantes 6457 G Montavon

UMR CNRS / U Nancy 7564 C Despas, A Walcarius

UPR CNRS 3079 F Fayon, D Massiot UPR CNRS 3079 Nantes 6230 F Fayon, D Massiot

UPR CNRS 3079 F Fayon, D Massiot

UMR CNRS / U P Janvier

B Bujoli, UMR CNRS / U Nantes 6230 B Bujoli, P Janvier

UMR CNRS / U Nantes 6502 P Deniard

Hôpital Cochin (Pr P Anract) Hôpital La Pitié Salpétrière

P Anract) CNRS / UCNRS Nancy (P6502 Hugues-Mousselard) U Nantes 6457F Fayon, UMR UMR CNRS / UCNRS Nantes Hôpital Cochin (Pr P Anract) UMR / U 6502 Nancy 7564 Hôpital UMR / U7564 Nantes 6457 UMRCochin CNRS /(Pr U Nantes D Massiot Hôpital La PPitié Salpétrière Hôpital La Pitié Salpétrière C Despas, A Walcarius C Despas, A Walcarius G Montavon P Deniard G Montavon Deniard UMR CNRS / U Nantes 6230 (P Hugues-Mousselard) (P Hugues-Mousselard) B Bujoli, P Janvier

UMR CNRS / U Nantes 6502 P Deniard

Hôpital Cochin (Pr P Anract) Hôpital La Pitié Salpétrière (P Hugues-Mousselard)

 Grants:Hôpital Cochin (Pr P Anract) Hôpital La Pitié Salpétrière

UMR CNRS / U Nantes 6502 P Deniard

(P Hugues-Mousselard)

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