ISTITUTO ORTOPEDICO G. PINI

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1 ISTITUTO ORTOPEDICO G. PINI
UNIVERSITA’ DEGLI STUDI DI MILANO Classificazione e indicazione all’uso dei fattori di crescita in Traumatologia G.M. Calori Biella, 5 Giugno 2009

2 Clinical Evidence vs Clinical Experience
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Clinical Evidence vs Clinical Experience Levels of evidence PRCT (14%) Cohort studies (20%) Case control (10%) Retrospective case series (56%) Experience/Opinion (0%)

3 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
Dott. Marshall R. Urist Bone: Formation by Autoinduction. Science Nov 12;150(698):893-9.

4 OSTEOINDUCTION 1) CELL-MEDIATED 2) GF-MEDIATED
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita OSTEOINDUCTION Is the ability to stimulate bone tissue formation in a non-bone site and can be distinguished in: 1) CELL-MEDIATED 2) GF-MEDIATED

5 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
OSTEOINDUCTION CELL-MEDIATED In cell-mediated osteogenesis cell precursors are harvested from bone marrow, concentrated and grafted

6 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
OSTEOINDUCTION GF-MEDIATED In GF-mediated osteoinduction growth factors stimulate resident mesenchimal cells to differentiate in a chondro and osteblastic lineage

7 They are the main regulators of osteoblastic feedback
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita GROWTH FACTORS TGF-ß (1-5) and BMPs (1-16) belong to a family of proteins with similar amino-acidic sequences called TGF-ß superfamily They are the main regulators of osteoblastic feedback

8 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
GROWTH FACTORS TGF- ß TGF-ß controls the repairing process throughtout deposition of extracellular matrix with a mitogenic and chemotactic action Joyce ME et al. J Cell Biol 110: , 1990 Noda M, Camilliere JJ. Endocrinology 124: , 1989

9 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
GROWTH FACTORS TGF- ß Concentration of TGF- ß in bone tissue and in platelets is 100 times greater than in the other tissues Joyce ME et al. J Cell Biol 110: , 1990 Noda M, Camilliere JJ. Endocrinology 124: , 1989

10 Transition- osteoblast Osteozytic osteoblast
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita GROWTH FACTORS PDGF BMP-7 Osteonectin BDGF Collagen type I Vitamin D sialoprotein Osteocalcin Mesenchymal stem cell Osteo- progenitor cell Pre-osteoblast Transition- osteoblast Secreting osteoblast Osteozytic osteoblast Osteocyte IGF-I / IGF-II aFGF / bFGF TGF-B1 / TGF-B2 LIF BMP-2 / BMP-3 Growth Factors have a combined, sequencial and stadium-specific action

11 Cellula osteoprogenitrice
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita GROWTH FACTORS Mesenchimal stem cell Cellula osteoprogenitrice Osteoblast Proliferative effect Differentiative TGF-ß IGF PDGF FGF BMP Mohan S, Baylink DJ. Clin Orthop 263:30-48, 1991

12 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
The meeting between biotechnologies and the muscoloscheletal system involves many fields: scaffolds for bone defects treatment scaffolds for cartilage defects treatment synthetic growth factors platelets concentration systems marrow inhaled concentration and adsorbment systems stem cells in vitro expansion systems (?)

13 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
The meeting between biotechnologies and the muscoloscheletal system involves many fields: scaffolds for bone defects treatment scaffolds for cartilage defects treatment synthetic growth factors platelets concentration systems marrow inhaled concentration and adsorbment systems stem cells in vitro expansion systems (?)

14 1980 - 2000 BMP genes identified Sampath & Reddi
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP genes identified Sampath & Reddi Commercial rights to molecules established Creative Biomolecules (later Stryker Orthobiologics) get OP1 (BMP-7) for bone Wyeth get BMP-2 for bone Both Boston - based Companies

15 1980 - 2000 Many BMPs are recognised (?up to 40)
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Many BMPs are recognised (?up to 40) Related by cysteine knot structure High amino acid sequence homology Share property of producing bone in non-osseous sites Genes found on different chromosomes Little difference between species (so human molecules can ligitimately and effectively be used on different lab animals) All members of TGFbeta superfamily of proteins

16 1980 - 2000 Human genome identified
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Human genome identified Plasmids manufactured containing gene sequences for BMPs Development of technology to produce rhBMP in cultured CHO cells

17 2000 - present Animal and human studies
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita present Animal and human studies Large scale commercial production Commercial licences granted rhBMP7 (OP1/ Osigraft) for long-bone non-union rhBMP2 (Inductos) for open fractures of the tibia rhBMP2 (Infuse) for spinal fusion

18 Animal Studies since 2001 Salkeld, Cook et al 2001 – dog ulna defect
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Animal Studies since 2001 Salkeld, Cook et al 2001 – dog ulna defect Mizumoto et al 2003– augmented callotasis with BMP7 Cook et al 2003– improved cartilage repair in dogs Improved tendon integration Dose ranging studies Seeherman (Wyeth – BMP2) – acceleration of fracture healing Blokhuis – (BMP7) acceleration of fracture healing Saito et al (BMP-2) - repair rabbit radial bone defect – 2009 induced periodontal regeneration in dogs

19 Animal Studies since 2001 Salkeld, Cook et al 2001 – dog ulna defect
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Animal Studies since 2001 Salkeld, Cook et al 2001 – dog ulna defect Mizumoto et al 2003– augmented callotasis with BMP7 Cook et al 2003– improved cartilage repair in dogs Improved tendon integration Dose ranging studies Seeherman (Wyeth – BMP2) – acceleration of fracture healing Blokhuis – (BMP7) acceleration of fracture healing Saito et al (BMP-2) - repair rabbit radial bone defect – 2009 induced periodontal regeneration in dogs

20 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
Repair of Articular Cartilage Defects with Osteogenic Protein-1 (BMP-7) in Dogs – Cook et al OP-1 After 6 weeks Control

21 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
Repair of Articular Cartilage Defects with Osteogenic Protein-1 (BMP-7) in Dogs OP-1 Control After 52 weeks

22 Human Studies for Trauma
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Human Studies for Trauma Friedlaender 2001 BESTT 2003 Australian Limb Salvage Series Others - ongoing

23 BMP-7 in Non Union - Friedlander et al.
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-7 in Non Union - Friedlander et al. JBJS (Am) 2001;83 Suppl 1(Pt1):s151-62 PRCT (Part blinded, multi-center) 124 Tibial Non unions Excluded: Unreliable, Infected, envelope problems etc 2 groups Autograft + IM Nail (Control) BMP-7 + IM nail

24 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
Summary of Safety*: *Friedlaender et. al, JBJS, Vol. 83-A, No. 4, April 2001.

25 Friedlander results (21% vs 3%) p=0.002
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Friedlander results More “atrophic” (p=0.048) in OP-1 (randomisation) Comparable union rates at 9 months Concluded BMP-7 comparable to autograft 20% chronic donor pain in autograft group Osteomyelitis higher in control group (21% vs 3%) p=0.002 Potential Criticisms: 1/3 loss to follow up at 2 years Heterogenous group (50% prev IMN, 40% prev autograft) Non stratified

26 Evidence for BMPs in Acute Fracture Care
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Evidence for BMPs in Acute Fracture Care

27 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
BMP-2 Evaluation in Surgery for Tibial Trauma Trial (BESTT) - Govender et al BMP-2 for treatment of Open Tibial fractures: PRCT (450 Patients) JBJS(A) A(12): 49 centres, 11 countries 450 Patients, Stratified (1, 2 and 3A) and (3B) Excluded patients in whom “bone grafting anticipated” 3 groups IM Nailing Low concentration BMP-2 (0.75mg/ml) High concentration BMP-2 (1.5mg/ml) Outcome measure 2y intervention within 12 months due to delayed or non union.

28 3B Open Tibia Subgroup Need for bone graft
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 3B Open Tibia Subgroup No significant difference % reamed and unreamed (p=0.14) Outcome measures : Need for bone graft Control 13/65 (20%) BMP-2 1/66 (2%) p0.0005, relative risk reduction 90% Invasive secondary procedures Control 18/65 (28%) BMP-2 6/66 (9%) p=0.0065, relative risk reduction 68% Infection Control 26/65 (40%) BMP-2 13/66 (21%) p=0.02, relative risk reduction 48% Faster clinical healing 95 v 126 days in BMP-2 group

29 Results 6 weeks 14 weeks 52 weeks 26 weeks
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Results Anteroposterior radiographs of a twentynine- year-old man made at visits ranging from six to fifty weeks postoperatively. The patient had sustained an open fracture of the left tibia (Gustilo-Anderson type IIIB, AO type C1) in a motorcycle accident. Treatment included unreamed locked nailing (Synthes AO 9-mm nail) and a 1.50- mg/mL rhBMP-2 implant. The fracture was considered to be healed at twenty weeks by the treating surgeon and to be united at twenty-six weeks by the independent radiology panel. 6 weeks 14 weeks 52 weeks 26 weeks * BESTT Study Group

30 “Son of BESTT” - Swiontowski et al
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita “Son of BESTT” - Swiontowski et al rhBMP-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am Jun;88(6): 450 BESTT patients plus 60 US centre patients Sub group analysis 3A/3B fractures (n=131) Reamed Nailing (n=113) Only analysed 1.5mg/ml (High dose/concentration) treatment group Trial not set up or powered for subgroup analysis.

31 Results BESTT Secondary Intervention Control 46% 0.75mg/ml BMP-2 37%
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Results BESTT Secondary Intervention Control 46% 0.75mg/ml BMP-2 37% 1.5mg/ml BMP-2 26% dose/response relationship (p=0.0004) 44% reduction in 2y intervention between Control and High dose Greater overall success in BMP groups esp High Faster wound healing at 6/52 p=0.001 More healed P=0.0008 Faster Healing P=0.002 Lower infection in severe fractures (3B) in BMP groups. P=0.02

32 BMP-2 + Allograft vs AICBG - Jones et al
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-2 + Allograft vs AICBG - Jones et al rhBMP-2 and allograft compared with Autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. (BESTT ALL) Study Group 2006 JBJS (A)July 2006 RCT N=30 (2/3 IM nail), (1/3 Ex fix) 2 Groups of 15 15 Secondary autologous graft at 6-12 weeks 15 Allograft chips with BMP-2 1-7cm defects, 20% drop out rate/loss to follow up,15% violated protocol (LISS 2/IMN 1) or Demineralised Bone Matrix (1) “Success” rate in BMP-2 87%, Control 67%. (p>0.05) 13% of failures in control were broken cross screws! Suggested equivalence of Auto vs Allo+BMP-2

33 BMP-7 in Tibial fractures – Maniscalco et al
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-7 in Tibial fractures – Maniscalco et al Healing of Fresh tibial fractures with OP-1 a preliminary report Acta Biomed Ateneo Parmenese 2002;73:27-32. Ex fix +BMP-7 vs Ex fix + Autologous graft 2 randomised groups BMP-7 (n=7) control (n=7). No statistical difference They all healed! Involved opening closed fractures Undersized study

34 BMP-7 in Open Tibial Fractures – McKee et al
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-7 in Open Tibial Fractures – McKee et al BMP-7 on healing of open tibial fractures results of multicenter PRCT OTA 2002, AAOS 2003 N=62 per group Favoured early weight bearing in BMP-7 group Less pain with activity P=0.04 Reduced secondary intervention in BMP-7 group (13% vs 27%) p=0.02

35 BMP-7 in Distal Tibial Fractures + EF – Ristinemi et al
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-7 in Distal Tibial Fractures + EF – Ristinemi et al rhBMP-7 accelerates the healing in distal tibial fractures treated by external fixation JBJS Br 2007 Feb 89(2): 20 in each group, case control study Faster healing p<0.03 Faster return to work p<0.018 Shorter time in external fixator p<0.037 Lower secondary intervention in BMP-7 group 10% vs 35% CONCLUDED BMP-7 ACCELERATES ACUTE FRACTURE UNION

36 Spinal Fusion Evidence
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Spinal Fusion Evidence

37 12 RCTs of BMPs in Spinal Fusion
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 12 RCTs of BMPs in Spinal Fusion 9 USA, 1 Sweden,1 Canada, 1 Japan/USA Ecosse 1 France 0 (Full Time) 4 Anterior, 7 Posterolateral, 1 Neck. BMP-2 n=631 More effective than autograft for radiographic fusion p<0.05 95% vs 89% Burkus 2002 99% vs 76% in Burkus 2005 BMP-7 n=56 No significant difference to autograft in fusion

38 Australian Limb Salvage
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Australian Limb Salvage 163 cases FU 15 mo ave. Heterogeneous group – OP1 + AutoG, AlloG, Fillers. OP1 alone: 36 cases. 40 had previous AutoG. 39 failures overall 30% failure for non union group (28/113)

39 Bone loss - THA revision
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Bone loss - THA revision

40 July 2006 - Impaction grafting review
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita July Impaction grafting review

41 July 2006 - Impaction grafting review
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita July Impaction grafting review

42 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
GFs vs infection

43 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
July 2006 – Chen et al

44 July 2006 – Chen et al Conclusions
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita July 2006 – Chen et al Conclusions

45 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
PRP PRP is a source of aspecific autologous GFs able to stimulate the repairing process in the application site. It has the same effects of the haematoma, empowered by high concentration of trombocites.

46 (Platelet Rich Plasma) (Platelet Poor Plasma)
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita PRP Throughout centrifugation PRP is divided from the other blood fractions Red blood cell PRP (Platelet Rich Plasma) PPP (Platelet Poor Plasma)

47 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
PRP Activated platelets degranulate and release various GF and cytokines: Platelet Derived Growth Factor PDGF-ßß PDGF-aa PDGF-aß Transforming Growth Factor beta TGF-ß1 TGF-ß2 Vascular Endothelial Growth Factor VEGF Epithelial Growth Factor EGF Insuline Growth Factor IGF1-2

48 PRP INDUCE OSTEOGENESIS
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita PRP Platelet Derived Growth Factor PDGF-ßß PDGF-aa PDGF-aß Transforming Growth Factor beta TGF-ß1 TGF-ß2 Vascular Endothelial Growth Factor VEGF Epithelial Growth Factor EGF Insuline Growth Factor IGF1-2 INDUCE OSTEOGENESIS Activated platelets degranulate and release various GF and cytokines:

49 PRP INDUCES ANGIOGENESIS
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita PRP Activated platelets degranulate and release various GF and cytokines: Platelet Derived Growth Factor PDGF-ßß PDGF-aa PDGF-aß Transforming Growth Factor beta TGF-ß1 TGF-ß2 Vascular Endothelial Growth Factor VEGF Epithelial Growth Factor EGF Insuline Growth Factor IGF1-2 INDUCES ANGIOGENESIS

50 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

51 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
DBM Bae et al.Spine ;31:

52 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
WHAT GFs ? BMP-2 PRP BMP-7

53 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
WHAT GFs ? BMP-2 PRP BMP-7

54 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
WHAT GFs ? Mesenchimal cells Mesenchimal cells BMP-2 DBM Osteoblast Mesenchimal cells, in presence of BMP-2 only (not charachterized by a powerful mitogenic effect), differentiate but not multiply BMP-2 Osteoblasts Mesenchimal cells in presence of DBM (BMP + TGF-  and other GFs) differentiate and multiply themselves

55 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
WHAT GFs ? BMP-2 PRP BMP-7

56 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
PRP It does not exist any controlled randomised study pro PRP. Its efficacy, based on shared phisyopathologic remarks, has to be demonstrated in the muscoloscheletal field.

57 Tissue Engineering Tools
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Tissue-Engineering: PRP PRP = osteopromotive agent It promotes the cellular division (mitogenesis) Not specific for the bone cell Only partially involved in the cascade of events that leads to bone neoformation and that follows the osteoblast differentiation Unable to induce by the bone neoformation Unable to promote the differentiation of stromal cells

58 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
WHAT GFs ? BMP-2 PRP BMP-7

59 Tissue Engineering Tools
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Tissue-Engineering: BMP-7 BMP-7 = osteoinductive agent BMP are the only growtgh factors with a recognized ability to induce the differentiation of of osteoprogenitor cells in a pre-chondroblastic and pre-osteoblastic lineage It stimulates bone neoformation Urist MR. Science 159: , 1965 Wozney JM. Mol Reprod Devel 32: , 1992 Chen D. Growth Factors 22(4):233, 2004 Chaudhary LR. Bone 34(3):402, 2004

60 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
Only recombinant BMPs have level A grade of raccomandation according EBM criteria

61 End-point: evaluation of osteoinduction in rats
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita PRP vs BMP-7 End-point: evaluation of osteoinduction in rats

62 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
Bone formation after 50gg of 20mm3 at Bio0ss or 20 mm3 at rib 10 µl of rhBMP-7 or 20 µl PRP

63 ISTITUTO ORTOPEDICO G. PINI UNIVERSITA’ DEGLI STUDI DI MILANO
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita ISTITUTO ORTOPEDICO G. PINI UNIVERSITA’ DEGLI STUDI DI MILANO

64 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
STUDY PURPOSE Compare the efficacy of BMP-7 and PRP as bone stimulating agents in the treatment of NU Establish a real alternative to autograft, golden standard for this treatment

65 This gap was classified in 3 groups:
G.M. CALORI L’utilizzo dei fattori di crescita nelle Pseudoartrosi When in the atrophic non-union there was a bone loss that needed a scaffold to correct the deformity This gap was classified in 3 groups: Group A: gap < 1 cm patients (45.83%) Group B: gap from 1 to 3 cm patients (39.16%) Group C: gap > 3 cm patients (15.0%)

66 RESULTS

67 G.M. CALORI L’utilizzo dei fattori di crescita nelle Pseudoartrosi
12/60 (20%) 4/60 (6,6%) Re-interventions *2 21/60 (35%) 23/60 (38,3%) Previous autografts 19/60 (31,7%) 8/60 (13,4 %) Failures *1 4±0,61 3,5±0,48 Clinical Healing time (months)- mean ± SD 41/60 ( 68,3%) 52/60 (86,6%) Clinical Healing rate *1 9±0,52 8±0,48 RX Healing time ( months ) - mean ± SD RX Healing rate *1 48/60 (80 %) 40/60 (66,6%) Synthesis Change 2,8±0,74 2,6±0,62 N° Praevius surgery - mean ± SD 19,4±1,45 20,2±1,34 NU duration (months) - mean ± SD 19 Tibia 8 Femur 16 Humerus 8 Ulna 9 Radius 15 Tibia 10 Femur 15 Humerus 12 Ulna 8 Radius Site NU 42,5±1,76 46,4±1,98 Age (y) mean ± SD 60 N evaluable patients (9 months Follow up) PRP rh BMP-7 * Χ2 test = 5.78 with 1 degree of freedom, p = ; significant * Χ2 test = 4.62 with 1 degree of freedom, p = ; significant

68 G.M. CALORI L’utilizzo dei fattori di crescita nelle Pseudoartrosi
rhBMP-7 PRP Number of patients 60 Gender (Male/Female) 32 / 28 35 / 25 Age (years,median + range) 44 (19-65)* 41 (21-62)* Nicotine use % 33.3% 28.3% Open fracture at injury 4 1 grade II 2 grade IIIa 1 grade IIIb 5 1 grade I Duration of non-union (months, median ± SD ) 20,2±2,35 19,2±2,86 Number of previous surgeries (median + range) 2 (1-5) Prior autograft implementation 23/60 (38,3%) 21/60 (35%)

69 rhBMP-7 Group PRP Group n Non union site tibia 15 5 IMN 8 ORIF 2 EF 19
Fixation treatment prior to our intervention Fixation revision during our intervention Summary of fixation treatment  Non union site Initial fixation after injury (preserved during our intervention) Fixation revision after non union tibia 15 1 IMN 2 ORIF 1 EF 2 IMN 2 ORIF 4 IMN 5 IMN 8 ORIF 2 EF 1 ORIF 19 2 IMN 2ORIF 3 IMN 7 IMN 10 ORIF 2 IMN 4 ORIF 6 ORIF femur 10 1 EF 2 IMN 8 3 ORIF 4 ORIF humerus 3 EF 16 7 ORIF 5 EF 3 ORIF 1 EF 1 IMN 5 ORIF 4 EF ulna 12 3 ORIF 2 K-W 1 IMN 1 K-W radius 3 ORIF 2 K-W 9 2 K-W

70 FAILURES BMP-7 (8/60) PRP (19/60)
G.M. CALORI L’utilizzo dei fattori di crescita nelle Pseudoartrosi FAILURES BMP-7 (8/60) 1 case: new trauma with Ex Fix failure and re-fracture 4 cases: sepsis 2 case: absence of callus formation 1 case: poor callus at the 9th month PRP (19/60) 5 cases: sepsis 9 cases: absence of callus formation 1 case: new fracture in severe osteopenia 4 cases: poor callus at the 9th month

71 Radiographic and clinical failure rate
G.M. CALORI L’utilizzo dei fattori di crescita nelle Pseudoartrosi Radiographic and clinical failure rate 86,7% = NU healing rate 52 (86,7%) 8 (13,3%) 41 (68,3%) P = 0, SIGNIFICANT 19 (31,7%)

72 G.M. CALORI L’utilizzo dei fattori di crescita nelle Pseudoartrosi
NU Re - Intervention 3 57 13 rhBMP-7: 5% VS PRP: 21% p= SIGNIFICANT 47

73 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
89,7% = NU healing rate

74 SUMMARY Minibattle: PROs GFs Vs BMPs pros & cons
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita SUMMARY Minibattle: PROs GFs Vs BMPs pros & cons AGF (PRP) Contains many GFs (FGF, TGFbeta,ILF,PDGF,VEGF) that could act sinergistically Well documented in soft tissue reconstruction and CMF surgery Good handling, diffused technique Rh-BMPs The only GFs with proven efficacy in trauma conditions (EBM-criteria) Standardized dose: reproducibility of results Drugs =scrutined by Health authorities for quality, efficacy, safety

75 SUMMARY Minibattle: CONs GFs Vs BMPs pros & cons
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita SUMMARY Minibattle: CONs GFs Vs BMPs pros & cons AGF (PRP) No BMPs contained = not osteoinductive Sistem’s Variability = concentration/activity PLT variability = conflicting literature evidence Lack of randomized trials in Ortho-trauma “manpower” cost non quantifiable Legal problems (preparation to be done by haematologists only ) Rh-BMPs Even present, still few randomized CTs Limited approved indications High aquisition costs Low adoption, scarce confidence

76 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

77

78 Forearm biosseus fracture PREVIOUS TREATMENT
C.A yrs Forearm biosseus fracture PREVIOUS TREATMENT ORIF SYNTHESIS -> Failure BONE IMPLANT Synthesis and cast -> Failure: Necrotic settic NU Therapeutic program 1st STEP: NU site resection cultural exams antibiotic therapy Axial external fixator (4 wks)

79 Forearm biosseus fracture PREVIOUS TREATMENT
C.A yrs Forearm biosseus fracture PREVIOUS TREATMENT ORIF SYNTHESIS -> Failure BONE IMPLANT Synthesis and cast -> Failure: Necrotic settic NU Therapeutic program 2nd STEP: Fixator removal Vascolarized fibular grafting ORIF

80 Forearm biosseus fracture PREVIOUS TREATMENT
C.A yrs Forearm biosseus fracture PREVIOUS TREATMENT ORIF SYNTHESIS -> Failure BONE IMPLANT Synthesis and cast -> Failure: Necrotic settic NU Therapeutic program 2nd STEP: Fixator removal Vascolarized fibular grafting ORIF

81 Forearm biosseus fracture PREVIOUS TREATMENT
C.A yrs Forearm biosseus fracture PREVIOUS TREATMENT ORIF SYNTHESIS -> Failure BONE IMPLANT Synthesis and cast -> Failure: Necrotic settic NU Therapeutic program 2nd STEP: Fixator removal Vascolarized fibular grafting ORIF

82 Forearm biosseus fracture PREVIOUS TREATMENT
C.A yrs Forearm biosseus fracture PREVIOUS TREATMENT ORIF SYNTHESIS -> Failure BONE IMPLANT Synthesis and cast -> Failure: Necrotic settic NU Therapeutic program 3rd STEP: R-U distal prosthesis acc. to Herbert

83 Forearm biosseus fracture PREVIOUS TREATMENT
C.A yrs Forearm biosseus fracture PREVIOUS TREATMENT ORIF SYNTHESIS -> Failure BONE IMPLANT Synthesis and cast -> Failure: Necrotic settic NU Therapeutic program 3rd STEP: R-U distal prosthesis acc. to Herbert

84 WHAT’S MORE … rh-BMP7 + MSC EXPERIENCE
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita WHAT’S MORE … rh-BMP7 + MSC EXPERIENCE

85 ISTITUTO ORTOPEDICO G. PINI UNIVERSITA’ DEGLI STUDI DI MILANO
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita ISTITUTO ORTOPEDICO G. PINI UNIVERSITA’ DEGLI STUDI DI MILANO Protocollo di Studio: STUDIO CLINICO INDIPENDENTE SULLA EFFICACIA E SICUREZZA DELL’IMPIEGO DI rhBMP-7 (OP-1) IN ASSOCIAZIONE CON CELLULE STAMINALI MESENCHIMALI NEL TRATTAMENTO DELLE PSEUDOARTROSI COMPLESSE DELLE OSSA LUNGHE

86 “The Diamond Concept” Osteogenic cells Osteoconductive scaffolds
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Osteogenic cells Osteoconductive scaffolds “The Diamond Concept” T. Einhorn - P. Giannoudis - D. Marsh Growth factors Mechanical environment

87 WHY NOT use both together?
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Growth factors and in particular BMPs make their action on mesemchymal cells so WHY NOT use both together? Mesenchimal stem cell Cellula osteoprogenitrice Osteoblast BMP TGF-B Saito et al 2005 “Accelerated bone repair with the use of a synthetic BMP-2-derived peptide and bone-marrow stromal cells. “ J Biomed Mater Res A ,2005 Jan 1;72(1):77-82 A denser and earlier ectopic bone formation was achieved when BMP were coimplanted with syngeneic rat bone-marrow stromal cells into a rat's calf muscle BMP TGF-B

88 NON UNION – C.A. Pre-op II.2007 Motorcycle accident
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – C.A. Pre-op II.2007 Motorcycle accident -> radial fracture -> plating + TEN II.2008 -> RADIAL ATROPHIC NU

89 NON UNION – C.A. 10.II.2009 devices removal + PSA 3 cm resection
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – C.A. 10.II.2009 devices removal + PSA 3 cm resection new synthesis with plate + allograft + mesenchymal stem cells (CELLECT) + OP-1 (1 vial)

90

91 NON UNION – C.A. 1 month 1 Month Clin. Eval. : no pain ROM : complete
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – C.A. 1 month 1 Month Clin. Eval. : no pain ROM : complete Rx : initial callus formation

92 NON UNION – P.G. Prec. VII.2002 M. 80 Yrs Street accident
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – P.G. Prec. VII.2002 M. 80 Yrs Street accident -> Diafisary femoral fracture OP Screw-plate

93 NON UNION – P.G. Prec. After 12 months Clinical ev: Pain
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – P.G. Prec. After 12 months Clinical ev: Pain Reducted function Rx: No good callus formation -> diafisary femoral NU

94 NON UNION – P.G. Pre-op After 2 years Clinical ev: Strong Pain
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – P.G. Pre-op After 2 years Clinical ev: Strong Pain NO function Rx: Devices failure -> devices removal + NU site resection + Replating + OP1 + MSC

95

96 NON UNION – P.G. 1 month At 1 month Clinical ev: Moderate pain
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – P.G. 1 month At 1 month Clinical ev: Moderate pain Weight bearing ? Rx: Initial bridging callus

97 NON UNION – P.G. 6 months At 6 months Progression of the callus
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – P.G. At 6 months Progression of the callus 6 months

98 NON UNION – P.G. 9 months At 9 months Clinical ev: Moderate pain
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – P.G. 9 months At 9 months Clinical ev: Moderate pain Stability ROM complete Rx: Good callus

99 NON UNION – N.A. pre-op II.2006 Car accident
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – N.A. pre-op II.2006 Car accident -> forearm fracture (22 B) -> plating II.2007 -> radial plate removed -> ULNAR ATROPHIC NU (15 mm gap)

100 NON UNION – N.A. op 1.IV.2008 plate removal + PSA 3.5 resection
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – N.A. op 1.IV.2008 plate removal + PSA 3.5 resection new synthesis with plate + xenograft + mesenchymal stem cells (CELLECT) + Osigraft

101 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
NON UNION – N.A. op October 2008 New surgical Change device + Allograft (fibula shaft) Proximal Osteointegration

102 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
NON UNION – N.A. op

103 NON UNION – N.A. Post-op 1.IV.2008 plate removal + PSA 3.5 resection
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – N.A. Post-op 1.IV.2008 plate removal + PSA 3.5 resection new synthesis with plate + xenograft + mesenchymal stem cells (CELLECT) + Osigraft

104 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
NON UNION – N.A months

105 NON UNION – N.A. 12 months 12 months Clinical ev: No pain Complete ROM
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – N.A. 12 months 12 months Clinical ev: No pain Complete ROM Rx: Low bone integration

106 NON UNION – D.G. Pre-op -> 6 cm of shortening II.2008 M. 16 Yrs
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – D.G. Pre-op II.2008 M. 16 Yrs Motorcycle accident -> Medial femoral neck fracture -> screw fixation -> Varus deformity + AVN -> 6 cm of shortening III.2009 -> FEMORAL NECK NU + NECROSIS OF THE FEMORAL HEAD

107 NON UNION – D.G. post-op OP 2.XII.08 Femoral valgus
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – D.G. post-op OP 2.XII.08 Femoral valgus osteotomy sec. Pauwels Plating using blade-plate 135° + trocantheric fixation -> OP1 + mesenchymal stem cells + synthetic graft (cellect)

108 NON UNION – D.G. 1 month At 1 month Clinical ev: No pain Stability
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – D.G. 1 month At 1 month Clinical ev: No pain Stability ROM complete No weightbearing allowed 2,5 cm of shortening Rx: No progression of the femoral head necrosis No callus formation

109 NON UNION – E.E. Pre-op II.2008 Car accident
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – E.E. Pre-op II.2008 Car accident -> Pertrocantheric femoral fracture -> plating (in Egypt) -> implant failure + cut out of one screw X.2008 -> ATROPHIC NU

110 NON UNION – E.E. Post-op OP 3.XII.08 Devices removal +
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – E.E. Post-op OP 3.XII.08 Devices removal + NU cruentation + Replating using AO plate with trocantheric fixation + Medial allograft of neutralization + -> OP1 + mesenchymal stem cells + synthetic graft

111 NON UNION – Z.M. pre-op XII.2007 F. 61 Yrs Domestic accident
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – Z.M. pre-op XII.2007 F. 61 Yrs Domestic accident Severe osteoporosis -> femoral neck and sottotrocantheric fracture -> No diagnosis -> FEMORAL ATROPHIC NU -> 1° op: IMN + cement

112 NON UNION – Z.M. post-op OP 5.V.09 Nail and cement removal
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NON UNION – Z.M. post-op OP 5.V.09 Nail and cement removal Bone loss (6x3x3) Plating using blade-plate 135° + Allograft to fill the gap (femoral head) + Anterior Allograft of stabilization + -> OP1 + mesenchymal stem cells + synthetic graft (cellect)

113 NEVER FORGET …. GOOD STABILITY AND BONE CONTINUITY ARE CRUCIAL
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita NEVER FORGET …. GOOD STABILITY AND BONE CONTINUITY ARE CRUCIAL CONTACT OF OP-1 WITH VITAL BONE DO NOT JUDGE TOO EARLY DO NOT HOPE IN MIRACLE !! RECALCITRANT AND COMPLICATED NU CASES HAVE VERY LIMITED HEALING CHANCES AS REPORTED IN LITERATURE

114 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
CONCLUSION The discovery of GFs and rh-BMPs in particular opened the way to the combined Biological and mechanical approach in the traumatology field Rh-BMPs, growth and differenziation agents have the unique properties to stimulate new bone formation even in extraskeletal sites BMPs use, differently from other GFs is reccomanded in trauma applications (according to EBM criteria) Their success is NU is obviously linked to : An adeguate stabilization An adeguate soft tissue coverage Vascularity Vitality of bone Correct administration (adeguate haemostasis/containment, no drainage)

115 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
CONCLUSION FURTHER CHALLENGE REGARDING THE COMPLETE CHARACTERISATION OF PRP AND THE OPTIMISATION OF THEIR PREPARATION AND DELIVERY STILL NEED TO BE ADDRESSED. NOWADAYS THE BMP-7 RECOMBINANT TECHNOLOGY HAS PROVEN ITS SUPERIORITY AND REPRODUCIBILITY FURTHER STUDY ABOUT THE ASSOCIATION OF BMP-7 AND MESENCHYMAL CELLS ARE NECESSARY

116 PSA fase di silenzio biologico
G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita PSA fase di silenzio biologico “... IL TESSUTO DI PSEUDOARTROSI NON E’ DEL TUTTO PATOLOGICO MA POSSIEDE ANCORA LARGHE PROPRIETA’ EVOLUTIVE IN SENSO OSTEOGENETICO SE CORRETTAMENTE STIMOLATO ...” (Ruggeri F., Zinghi G.F., SIOT 1977)

117 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

118 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita
Biotecnologie