AOFAS Resident Review Course September 28, Sheldon S. Lin, MD Associate Professor North Jersey Orthopaedic Institute University Hospital

Transcription

1 Course September 28, 2013 Sheldon S. Lin, MD Associate Professor North Jersey Orthopaedic Institute University Hospital

2 Disclosures Research support from Biomimetic of Wright, Tissuegene Lab of UMDNJ has received research grants to study rhpdgf

3 Some Definitions Osteoconductive A surface which encourages bone cells to attach and grow Osteogenic Ability to produce new bone (need bone forming cells) Autologous bone patients own bone Allogeneic bone bone from a donor Autologous blood concentrates patients own blood Autologous bone marrow patients own bone marrow Osteoinductive Recruitment and stimulation of cells to form bone

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5 Osteoconductive materials Calcium phosphate Calcium sulphate CaP/collagen composites Demineralised bone matrix

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7 Osteogenic Materials Autologous bone Allogeneic bone (osteoconductive) Autologous blood concentrates Autologous bone marrow

8 Foot and Ankle Surgery Arthrodesis of Hindfoot and Midfoot joints remains the preferred method of managing arthritis and/or deformity of the foot and ankle. Given the mechanical role of the foot during gait fusion of hindfoot and midfoot joints is better tolerated than fusion of the hip or knee.

9 Delayed Union / Nonunion A review of ankle arthrodesis: predisposing factors to nonunion. Frey C et al Foot Ankle Int Nov;15(11): In this study, the nonunion rate was 41%, the worst in the literature. Majority of the patients were post-traumatic. Highest incidence in patients with plafond/talus fractures

10 Delayed Union / Nonunion Isolated Subtalar Arthrodesis Easley ME, Trnka HJ, Schon LC and Myerson MS J Bone Joint Surg Am May;82(5): consecutive isolated subtalar arthrodesis Overall nonunion rate = 16% Nonunion rate: Nonsmokers 8% Smokers 27% Nonunion rate in: Primary fusion 14% Revision fusion 29%

11 DM Population: Non-union rate of Hindfoot Fusion using Autologous Bone Triple Arthrodesis Papa and Myerson Stuart and Tisdel Graves 15-30% non-union rate

12 Delayed Union / Nonunion Current literature suggests overall nonunion rates for ankle/hindfoot fusions is > 15%. Nonunion rates are higher in: smokers, revision surgeries, posttraumatic arthritis (AVN) & DM In foot and ankle surgery, in spite of good surgical technique nonunions continue to be a common post-operative complication. Current data suggests that we need to continue to look at methods of improving union rates in hindfoot fusions.

13 Current developments to decrease nonunion rates Minimal soft tissue stripping Adequate exposure and complete removal of cartilage Perforation of bone to promote bleeding Adequate preparation of the fusion site

14 Current developments to decrease nonunion rates Rigid internal fixation with compression Further advancements are required to enhance fusion --Smokers --Revision surgery --Post traumatic arthritis (AVN)

15 Tissue Engineering BIOACTIVE SIGNALING MOLECULES e.g. PDGF, BMP, etc. Time Appropriate environment TISSUE REGENERATION Cells eg. osteoblasts fibroblasts chondroblasts Scaffolds e.g. β-tcp (CaPO4),Collagen Lynch, 2000

16 Bone Grafting Frequently used in conjunction with fusions Autograft is the gold standard, but Graft site pain and morbidity Limited availability Increased operative time, blood loss Alternatives to autograft are many and varied Allograft Demineralized Bone Matrix Synthetics +/- PRP

17 Use of Autologous Bone Grafting does come with a Price Iliac crest: Gold Std Stem cells Matrix Growth factors 340,000 patients undergo iliac crest harvest annually

18 Complication Rate of ILBG Iliac crest issues Pain Scarring Increased OR time Prolong hospitalization Increase blood loss Infection Hernias Surgical complications (fx, neuroma, hematoma)

19 Examples of Incisional Hernia after iliac crest bone graft harvest

20 Infection

21 Review of Literature Review of Literature Complications rate as high as 31% Subjectively, 27% of patients continue to feel pain at 24 months after surgery Gupta AR 2001

22 Common Questions? What growth factors are commercially available to Orthopedic Surgeon? How does use of these growth factors compare to use of autograft? What will be the financial cost of GF s? What is current Indications?

23 What growth factors are commercially available to Foot Ankle Surgeon today? Autologous Platelet concentrate(prp) Recombinant human bone morphogenic protein INFUSE: BMP-2 OP-1: BMP-7

24 What is Autologous Platelet Concentrate? Simply, it is a system designed to separate and concentrate platelets from the patients own blood at the point-of-care.

25 Platelet rich plasma: non fda

26 Autologous Platelet Concentrate When Activated, Platelets Release Growth Factors PLATELETS IN RESTING STATE (Discoid shape) Growth Factors in Platelets Platelet Derived Growth Factor (PDGF) Transforming Growth Factor- (TGF- ) Vascular Endothelial Growth Factor (VEGF) Insulin-like Growth Factor (IGF) Epidermal Growth Factor (EGF) PLATELETS IN ACTIVATED STATE (Pseudopod formation)

27 What is BMP? Marshall R. Urist, MD conducts experiments to find a way to remineralize bone 1965 Urist discovers that demineralized bone matrix (DBM) can induce new bone formation

28 BMP

29 DATA:Clinical Trials of PRP

30 How does use of these PRP compare to use of autograft? PRP-only two published clinical foot ankle papers Bibbo & Lin 2005 Coetzee & Pomoroy 2005

31 How does use of PRP compare to use of autograft? Coetzee and Pomoroy Foot Ankle Int 2005 Study design: syndesmotic fusion rates using PRP augmented bone grafting vs. historical control of non- PRP augmented bone graftingsyndesmosis during TAA 66 patients to 114 historical controls Radiographic union analyzed by either radiographs or CT scan

32 Level Three Evidence: Comparative Analysis: Historical control Bone graft (n=114) PRP and Bonegraft (N=66) Eight weeks Twelve weeks Six months Nonunion 61% 73% 85% 15% 76%* 94%* 97% 3%+ High risk Subset: smokers at six months Historical control-50% PRP and BG: 80%

33 Few prospective clinical papers of PRP- platelet gel or platelet rich plasma

34 Only clinical paper showing efficacy of PRP: D. Dallari et al 2007 JBJS Prospective, randomized, controlled study was performed, and a standardized clinical model was applied. Thirty-three patients undergoing high tibial osteotomy to treat genu varum Group A: lyophilized bone chips with platelet gel Group B: lyophilized bone chips with platelet gel and bone marrow stromal cells Group C: lyophilized bone chips without gel

35 Autologous Blood Concentrates Track record in bone is poor Lack of conclusive clinical data on the effectiveness Trend towards niche use in soft tissue The present study failed to show the clinical usefullness of isolated percutaneous platelet gel supplementation in long-bone non-unions treated by external fixation

36 Bone Marrow Aspirate

37 Autograft: The Gold Standard In Foot and Ankle Surgery* *Geideman, Early, Brodsky, FAI 2004 el

38 Hyer at JBJS 2013 Quantitative assessment of Osteblastic progenitor cells a. Iliac crest b. Tibia c. Calcaneus d. MSC found in all e. Bone marrow from iliac crest higher mean concentration

39 Hernigou JBJS 2006: Percutaneus Autologous Bone Marrow iliac crests Sixty pts w/ non- infected nonunions underwent bone marrow aspiration from both Samples concentrated on cell separator and injected Replacing PRP for bone applications Only one clinical paper exists Results: Union obtained in 53/60 pts Postive correlations between vol.of mineralized callus at 4 mos and number and concentration of CFUs The 7 pts who did not unite had significantly lower numbers and concentrations of CFUs

40 What is rhbmp-2? recombinant human BMP-2 Animal cells make human BMP-2 Solution of BMP-2 is filter sterilized, purified, placed into vials and freeze-dried

41 BMP History 1997 Clinical Trials started with rhbmp-2/acs for spine fusion and open tibia fractures BMP is destined to bring osteogenesis under the control of surgeons Urist MR, J NIH Res,1997

42 FDA (PMA) Approval rhbmp-2/acs (INFUSE Bone Graft) proven safe and effective 2002 FDA approval as an autograft replacement in spine fusion (ALIF) with specific interbody cages Based on clinical study with 411 patients 2004 FDA approval as an adjuvant for repair of tibia fractures with IM nail Based on clinical study with 299 patients 2006 Oral Maxillary Application

43 INFUSE Bone Graft is supported by more Level I clinical evidence than any other bone grafting technology. Only BMP product to demonstrate clinical efficacy in spine and trauma applications. 14 rhbmp-2 clinical trials. More than 1,750 patients enrolled in clinical trials.

44 NON FDA Label rhbmp2 in High Risk ankle and Hindfoot Fusion Bibbo et al FAI July fusions sites (69 patients) 64% smokers; 19% DM High energy 68%; AVN Talus32% 108 fusions (96% union) at mean 11 weeks (as assessed by CT scan) Ankle 10 wks, subtalar 12.3, TN 12.7 And calcaneocuboid at 10.9 weeks

45 NON FDA LABEL: Complication included non union in 5 of 112 joints (4%) Conclusion: rhbmp2 is effective adjunct in high risk ankle and hindfoot fusions

46 What are current FDA indications? PRP and BM -non regulated by FDA for this autologous product such as blood or autograft INFUSE(BMP-2)- open tibia fracture FDA approved and oral maxillafacial OP-1(BMP-7)- Humanitarian device excemption compassionate use for long bone non-unions Exogen- approved for fresh fracture and nonunion

47 Mechanism of Action BMA Bone marrow contains osteogenic progenitor cells. Implantation perceived to have potential to lead to effective bone regeneration more is better BMP MSCs migrate to fx site. Cause undifferentiated cells to multiply. BMP binds to receptors causing stem cells to differentiate to osteoblasts. Osteoblasts form new bone PRP Concentrates the body s natural growth factors to stimulate healing EXOGEN Caues nanomotion. Motion detected by integrins. Multiple pathways activated. One of the downstream effects is the production of COX-2. Effect of COX-2/PGE-2 is to enhance mineralisation, leading to bone.

48 Many Candidate non BMP s exists BUT NOT FDA LABELED FGF VEGF IGF PDGF Platelet rich plasma or platelet gel (PRP) is not rhpdgf rhpdgf is not PRP!!!! DKK INHIBITOR SCLEROSTIN PGE2 or 5LO inhibitor PTH1-34

49 Who should we treat? High risk subset (DM, smokers, steroid, elderly chemo patient, etc.) Patient with delayed union or non-union Patients with fracture known to have problems (i.e. Jones) FDA Label/ TELL THE PATIENT!!

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