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BoneAlbumin science summaryJanuary 2018
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January 2018
Zsombor Lacza MD PhD DSc – Founder, CEO and CSO
Arnold Fehér MD MSc – Director Business Development
Use of serum albumin coated allograft in bone replacement
2
What is BoneAlbumin?It is less known: albumin is a key for bone formation
Albumin is a bone protein!
• 30% of circulating serum albumin is of bone origin
• Albumin is the first protein secreted by regenerating osteoblasts
• Albumin is required for stem cells to proliferate in culture
• Normal allografts do not contain albumin as cleaning and preserving of bone eliminates the highly water soluble albumin content
• Simple replenishment of albumin improves allograft function
BoneAlbumin
• OrthoSera’s patent covered impregnation technology is applied on human allografts
• BoneAlbumin has scientific, clinical and market traction
Development of bone tissue cell types
Bone marrow derived stem cell (BMSC)
Osteo-blast
Osteo-cyte
Horváthy DB., et al. “Serum albumin as a local therapeutic agent in cell therapy and tissue engineering”. BioFactors 43.3 (2017): 315-330.
BoneAlbumin science summaryJanuary 2018
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In vitro studies: a summary
Albumin itself, in high concentrations (>10% weight) provides a proliferative
milieu for BMSCs on bone grafts.
Mode of action: activates the patient’s own stem cells’ proliferation on implanted allografts
4
In vitro: the problem of normal allograft is solved with albumin coatingBone marrow derived stem cells (BMSCs) proliferate
3rd day Normal allograft 18th day
Human bone marrow derived stem cells (BMSCs)
Surface of freeze-dried/lyophilized human bone allograft
Weszl M., et al. “Freeze-dried human serum albumin improves the adherence and proliferation of mesenchymal stem cells on mineralized human bone allografts”. Journal of Orthopaedic Research 30.3 (2012): 489-496.
BMSCsdisappear
BMSCsproliferate
Albumin coated allograft 18th day
BoneAlbumin science summaryJanuary 2018
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5
Human albumin effect on BMSCsBone marrow derived stem cells (BMSCs) proliferate
Weszl M., et al. (2012): 489-496.
183 1237 23
890
203
1,659
2,083
0
1,000
2,000
3,000
3rd day 18th day
# of BMSCs
6
Animal models: a summary
Albumin coating resulted in much faster bone healing and stronger bone
than without albumin.
BoneAlbumin science summaryJanuary 2018
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Animal study 1. – 3D microCT of rat femurThree representative cases: faster bone healing
Un
coat
edgr
aft
Alb
um
in co
ated
gra
ft
Skaliczki G., et al. “Serum albumin enhances bone healing in a nonunion femoral defect model in rats: a computer tomography micromorphometry study. International Orthopaedics 37 (2013): 741–745.
8
Animal st. 2. – ex vivo microCT of rat calvariaThree representative images: stronger bone
DBM = Demineralized Bone Matrix allograft
Horváthy DB., et al. “Serum albumin coating of demineralized bone matrix results in stronger new bone formation”. Journal of Biomedical Materials Research Part B, Applied Biomaterials 104 (2015): 126–132.
BoneAlbumin science summaryJanuary 2018
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Orthopedic clinical studies: a summary
BoneAlbumin resulted in faster bone healing than with autograft.
BoneAlbumin turns into living bone tissue leading to complete tissue healing.
Donor site pain is significantly lower with BoneAlbumin.
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1. First in human: Hip and knee prosthesis revision study
Representative SPECT-CT (labeling active osteoblasts) of a structural tibia at 1 year follow-up: osteoblast activity is apparent in the albumin coated allograft.
• Aseptic revision of hip and knee prosthesis
• Single group (no control group), variable shape and size of bone loss
• Individually ordered structural bone grafts
• Multiple surgeons and sites
• Started with 10 patients, now over 30
Klara T., et al. “Albumin coated structural lyophilized bone allografts: A clinical report of 10 cases”. Cell Tissue Bank 15.1 (2014): 89-97.
BoneAlbumin science summaryJanuary 2018
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Case report: revised-revision Tibia component loosening: living bone from graft
Intraoperative pictures of an albumin-coated structural tibia allograft at revision surgery at 19 months – triggered by minor trauma (household injury). Parts of the allograft are bleeding, a clear sign of living tissue. The overall structure is suitable to support a revised prosthesis without any further fixation.Klara T., et al. “The use of structural proximal tibial allografts coated with human albumin in treating extensive periprosthetic knee-joint bone deficiency and averting late complications. Case Report”. Orvosi Hetilap 156:2 (2015): 67–70.
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2. Double-blind controlled bone-tendon-bone harvest site filling study: the setup
• Very common sports (football, ski) surgery indication: ACL anterior cruciate ligament
• Young, healthy patient population
• Uniform shape and size of bone void
• Not a life-threatening indication, elective operation
• Allows a double-blind, well-controlled study design
Control arm:
• Patella: hematome
• Tibia: available autograft (standard of care)
Experimental:
• Patella: BoneAlbumin
• Tibia: available autograft mixed with BoneAlbumin
start 6 weeks 6 months
Physical + CTPhysical examinationOP
Schandl K., et al. “Bone-Albumin filling decreases donor site morbidity and enhances bone formation after anterior cruciate ligament reconstruction with bone-patellar tendon-bone autografts”. International Otrhopaedics 40 (2016): 2097–2104.
BoneAlbumin science summaryJanuary 2018
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Patella filling with BoneAlbumin vs. hematome at six months2. Bone-tendon-bone harvest site filling study
Control
BoneAlbumin
There is a significantly lower remaining defect size with a significantly denser remodeled bone in the BoneAlbumin group, indicating a nearly complete tissue healing.Schandl K., et al. (2016): 2097–2104.
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The real question: persistent pain2. Bone-tendon-bone harvest site filling study
*
**
*
Pain at the donor site was significantly lower in the treatment group both at kneeling and crouching, while standing pain was negligible in both groups.
Schandl K., et al. (2016): 2097–2104.
BoneAlbumin science summaryJanuary 2018
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Dental clinical studies: a summary
BoneAlbumin has the same easy application as other grafts.
BoneAlbumin granulate filling resulted in faster bone regeneration than xenografts.
After BoneAlbumin what remains is not just some ‘hard tissue’ – like with xenografts – but true bone which remodels and ages naturally during the course of the patient’s lifetime.
Post-operative pain is significantly lower with BoneAlbumin than with xenografts or even than without treatment.
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Application of BoneAlbumin in oral implantology
Stem cells entering
BoneAlbumin with a drop of patient
blood added
Implant in the new bone
Albumin activation
Stem cells entering Stem cells
Remodelling New bone
BoneAlbuminBone void
BoneAlbumin science summaryJanuary 2018
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1. Double-blind controlled 8th molar extraction socket filling studyIntraoperative pictures: Easy application
Extraction socketBoneAlbumin
granulate filling
• Extraction socket filling 3rd molar (wisdom tooth)
• Control I.: no treatment (standard of care)
• Control II.: BioOss (market leader bovine xenograft in Europe)
• Double-blind, randomised, self-controlled split-mouth design
• n=32
Under publication (2018)
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Post-operative pain at 7 days1. Extraction socket filling study: Lower pain
P < 0,05
Pain was significantly lower in the treatment group than in the other groups.Under publication (2018)
BoneAlbumin science summaryJanuary 2018
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Cone beam CT at 6 weeks1. Extraction socket filling study: Faster bone regeneration and lower demarcation on graft-host border than BioOss
Under publication (2018)
Non-resorbed graft Resembles ambient healthy bone structure
Incomplete filling
Control (no treatment) BioOss filling BoneAlbumin filling
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2. Double-blind controlled sinus lift studyHistology data: better transformation to new bone
In three cases BoneAlbumin
has completely resorbed and
was replaced by new bone.
• Sinus lift plus implantation at 6 months
• Control: BioOss (market leader bovine xenograft in Europe)
• Treatment: BoneAlbumin
• Double-blind, randomised, controlled, n=32
• 6 months follow up with histology and microCT
Quantitative micro-CT analysis showed that the newly formed bone in the BoneAlbumin group is closer to the native maxilla than that of the BioOss augmented group in several micro-morphometric parameters.
Kivovics M., et al. “Microarchitectural study of the augmented bone following ridge preservation with a porcine xenograft and a collagen membrane: Preliminary report of a prospective clinical, histological, and micro-computed tomography analysis”.International Journal of Oral and Maxillofacial Surgery. 46. . 10.1016/j.ijom.2016.10.010.
BoneAlbumin science summaryJanuary 2018
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BoneAlbumin turns into boneSeries of 100 dental cases
Gáspár L. “Experiences in the application of BoneAlbumin human allograft” Implantology, Dental Press (2018)
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BoneAlbumin competitive comparisonOsteoinduction is key advantage over both xenografts and synthetic grafts
Bone graftStructuralstrength
Osteo-conduction
Osteo-induction
Osteo-genesis
Autograft
Allograft
Frozen
Freeze-dried
Xenograft
Beta-TCP
+++ +++ +++low
+
++ no
no++
++ +
+
++ +++ no no
+++ + no no
Demineralized low nolow ++
BoneAlbumin ++ +++ +++ no
Growth Factors no no +++ no
Stem Cells no no ++ +++
Adepted from: American Academy of Orthopaedic Surgeons: Bone-graft substitutes: facts, fictions & applications
BoneAlbumin science summaryJanuary 2018
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BoneAlbumin summary
• BoneAlbumin is the next generation human bone graft with superiority proven in:
• Preclinical studies showing Stem Cell activation
• Animal studies showed superiority of albumin coating in every bone regeneration metric
• Human studies showed superiority in head-to-head comparisons with the market leader xenograft or even autograft
• Easy to use
• Works well both as a granulated bone filler as well as a large, structural graft
• Good remodelling signs on X-Ray and CT in each indication
• Less post-operative pain
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References
1. Weszl M., et al. “Freeze-dried human serum albumin improves the adherence and proliferation of mesenchymal stem cells on mineralized human bone allografts”. Journal of Orthopaedic Research 30.3 (2012): 489-496.
2. Horváthy DB., et al. “Serum albumin as a local therapeutic agent in cell therapy and tissue engineering”. BioFactors 43.3 (2017): 315-330.
3. Skaliczki G., et al. “Serum albumin enhances bone healing in a nonunion femoral defect model in rats: a computer tomography micromorphometry study. International Orthopaedics 37 (2013): 741–745.
4. Horváthy DB., et al. “Serum albumin coating of demineralized bone matrix results in stronger new bone formation”. Journal of Biomedical Materials Research Part B, Applied Biomaterials 104 (2015): 126–132.
5. Klara T., et al. “Albumin coated structural lyophilized bone allografts: A clinical report of 10 cases”. Cell Tissue Bank 15.1 (2014): 89-97.
6. Klara T., et al. “The use of structural proximal tibial allografts coated with human albumin in treating extensive periprosthetic knee-joint bonedeficiency and averting late complications. Case Report”. Orvosi Hetilap 156:2 (2015): 67–70.
7. Schandl K., et al. “Bone-Albumin filling decreases donor site morbidity and enhances bone formation after anterior cruciate ligament reconstruction with bone-patellar tendon-bone autografts”. International Otrhopaedics 40 (2016): 2097–2104.
8. Kivovics M., et al. “Microarchitectural study of the augmented bone following ridge preservation with a porcine xenograft and a collagen membrane: Preliminary report of a prospective clinical, histological, and micro-computed tomography analysis”. International Journal of Oral and Maxillofacial Surgery. 46. 10.1016/j.ijom.2016.10.010. – Abstract presented at ITI 2017, manuscript under revision
9. Ayoub AH., et al. “Clinical and Radiographic Evaluation of Socket Preservation Using Autologous Concentrated Growth Factors Enriched Bone Graft Matrix (Sticky Bone): A Case Report”. EC Dental Science 5.4 (2016): 1128-1135.
10. Ayoub AH., et al. “Ridge Rehabilitation in the Esthetic Zone Using Alloplastic Bone Graft and Albumin-Coated Allograft: A Case Report with 5 Year Follow Up”. EC Dental Science 14.5 (2017): 225-234.
11. Ayoub AH., et al. “Localized Maxillary Ridge Augmentation with Mineralized Plasmatic Matrix for Dental Implant Placement. International Journal of Preventive and Clinical Dental Research 4.2 (2017): 1-5.
12. Gáspár L. “Experiences in the application of BoneAlbumin human allograft” Implantology, Dental Press (2018)