BIOMATERIALI e FATTORI BIOMATERIALI e FATTORI di CRESCITA: DBM, BMPsdi CRESCITA: DBM, BMPs

Gabriela CiapettiLab for Orthopaedic Pathophysiology and

Regenerative MedicineIstituto Ortopedico RizzoliIstituto Ortopedico Rizzoli

BolognaBolognaRomeSpine2011

IL RACHIDE OGGIIL RACHIDE OGGICongresso internazionale - Roma 6-7 dicembre 2011

Properties of bone graft materials Properties of bone graft materials (PG Wang, Seminars in Spine Surgery, 2003;15:460)

Bone graft substituteOsteogenic

cellsOsteoinductive

factorsOsteoconductive

matrixInitial

biomechanical strenght

Donor-site morbidity

Autogenous bone-cancellousAutogenous bone-cancellous +++ ++ +++ - ++

Autogenous bone- corticalAutogenous bone- cortical + + + +++ ++

Allograft boneAllograft bone - + + ++ -

Synthetic osteoconductive materialsSynthetic osteoconductive materials - - +++ + -

Demineralized bone matricesDemineralized bone matrices - ++ + - -

Osteoinductive growth factorsOsteoinductive growth factors - +++ - - -

Autologous platelet concentrateAutologous platelet concentrate - ++ - - -

why biologics for spinewhy biologics for spine

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

Disc degeneration is a common disorder: 97% of individuals 50 years or older show disc degeneration (autopsy study, 600 cases)

R Kandel, Europ Spine J 2008;17:S480

spine fusions and joint arthrodesis require adjuvant treatment with bone grafts or substitutesstrategies used currently for symptomatic degenerative disc disease not effectiveregenerative medicine/tissue engineering appear promising

NP NP easier to be replaced..early symptomatic degeneration.. use cells alone

AFAF structurally complicate because of mechanical work to accomplish biomaterials injection can restore disc volume but hardly its function……

functionality is restored by injecting ECM components interacting with disc cell…butbut ….. in advanced disc degeneration no viable cells left to be stimulated

better outcome achieved if biomaterials are used for matrix-assisted cell transfer, i.e. injected as a mixture of cells and a gel-like matrix, preventing leakage of cells

regenerative medicine for IVDregenerative medicine for IVD

48 weeks

Sakai D, Biomaterials 2003;

Yoshikawa T, Spine 2010

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

NL Nerurkar, J Biomech 2010;43:1017

alginate/chitosan fibers

carbossimetilcellulose gel

atelocollagen honeycomb electrospun, nanofibrous

nanofibrous+ agarose NP

NP cells in alginate

hyaluronic+ nanofibrousPCL multilamellar AF & DBM AF cells in PGA mesh

Categories of biomaterialsCategories of biomaterialsProtein-based materials : Collagen, Fibrin, Laminin (Matrigel TM), Gelatine

Polysaccharide-based materials Agarose, Alginate, Hyaluronan, Chitosan, Cellulose

Artificial polymers Polylactic acid, Polyglycolic acid, Carbon fibers, Dacron (polyethyleneterephtalate), Teflon (polytetrafluoroethylene), Polyurethane, Polybutyric acid, Polyethylen-methacrylate, Calcium phosphates

 C. Merceron, Joint Bone Spine 2008; 75:672 which materials?which materials?

scaffoldsscaffoldsTechnical scaffold demands can be qualitatively summarized as the 4Fs:

Form, Function, Fixation, and Formation

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

SJ Hollister, Tissue Eng 2011;17:479

L Nandan, Nature Materials 2009;8:986

DBMDBM

Demineralized bone matrices generated by acid extraction of allograft bone, with loss of mineralized components, but keeping type I collagen and many growth factors DBM: no structural strenght but osteoconductiveosteoconductive and osteoinductiveosteoinductive, due to bone morphogenetic proteins (BMPs) Commercial DBMs (gel, flex strips, putty) variable in osteoinductive potential due to different BMP content

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

Efficacy shown in posterolateral spinal fusion using DBMs alone or with autograft, or as bone graft extenders in adult patients and adolescent patients with scoliosis,

butefficacy in anterior spinal fusion not testified enough, and structural carrier recommended

from clinics

demineralized bone matrix gelatine

Hyal

Y Zhuang, Biochem Biophys Res Comm 2011;407:327

Bone Morphogenetic ProteinsBone Morphogenetic Proteins(M. Urist, 1965)(M. Urist, 1965)

Recombinant human BMP2 (rhBMP-2rhBMP-2) and recombinant BMP7 (osteogenic protein 1 = OP-1OP-1) are soluble a carrier (bovine collagen or collagen sponge) needed not to diffuse away from the fusion site ceramic granules often needed to provide structural strenght and osteoconduction

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

RRhBMP2hBMP2: the most commercially successful BTE product, up to 25% of all spinal fusion procedures + a variety of off label applications (up to 83% of rhBMP2 use estimated to be off label)OP-1OP-1: bone substitute and bone extender in spinal fusion

from clinics

Growth Differentiating Factor-5 (GDF-5GDF-5): ECM synthesis and disc height

restoration

the success limited by availability of viable cells: suitable primarily for early/moderate stages of IDD

this stimulation is only short-term

adadvverseerse reactionsreactionsheterotopic bone formation in tibial

fracture repair

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

High BMP dose/concentration may result in inflammation, soft tissue swelling, radiculitis, unwanted ectopic bone formation

AL Shimer, Injury 2009;40:S32

significant complications with rhBMP2: • dysphagia, airway compression, postoperative neck hematoma in cervical spine fusion• heterotopic bone formation in spinal canal • osteolysis

from clinics

subchondral cyst formation

osteolysis

E Carragee, Spine J 2011;11:471

E Carragee, Annual Meeting of North American Spine Society, November 2-5, 2011, Chicago

use of high doses of recombinant bone morphogenetic protein-2 in posterior lumbar fusion could be associated with an increase in cancer rates (518 patients: 239 treated with high-rhBMP2 vs 22a with local graft – 20 cancers vs 5 at 2-3 yrs FU)

K Masuda, Tissue Eng Part B, 2010;16:147

present challengesAApplicationpplication of tissue engineered products in vivo has great influence on success in clinics

insertion depends on whether it is a complete disc or only part of it i.e. invasive surgery vs cell therapy via needle

Calcification of the endplateCalcification of the endplate: major problem for the success of cell-based therapies for disc regeneration

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

Disc nutritionDisc nutrition: : disc cells require nutrients to function and maintain viabilityloss of nutrient supply = low oxygen & low glucose for ATP generationglucose lower than 0.5 mM: cell death lactic acid accumulation contributing to disc degeneration

HHow performance of disc cell therapies can be monitored ow performance of disc cell therapies can be monitored inin humans humans in vivoin vivo patient clinical symptoms, but changes in disc

composition, cell no/viability, biomechanics?disc height: by radiological imaging, but repeated X-rays for

monitoring changes not possible in humansMRI: ideal method for changes in disc hydration/composition

because non invasive nature/routine clinical use

cconclusions…perspectivesonclusions…perspectives

the overlapping fields of tissue engineering and regenerative medicine (TERM) date to the late 1980s/early 1990s: the field is a little over 20 years old

Yet, with the exceptions of autologous chondrocyte implantation (ACI), Infuse® and OP-1®, no orthopaedic product related to TERM has reached the market, despite the remarkable regenerative power of bone

CH Evans, Tissue Engineering Reviews 2011;17(6)

Fisiopatologia Ortopedica e Medicina Rigenerativa - IOR

Early symptomatic degeneration: cell therapy+scaffold for NPEarly symptomatic degeneration: cell therapy+scaffold for NP (AF integrity and disc nutrition required)

Late degeneration: fusion with biologics Late degeneration: fusion with biologics ((++ instrumentat instrumentation when ion when neededneeded))

Hyerarchical scaffolds: 4F and ………Hyerarchical scaffolds: 4F and ………

low rhBMP-2low rhBMP-2 dosing, interbody device optimizing, endplate integrity maintenance

Fisiopatologia Ortopedica e Medicina Rigenerativa - IORFisiopatologia Ortopedica e Medicina Rigenerativa - IOR

thanks for your attention