Use of serum albumin coated allograft in bone replacementdynadental.com/app/uploads/2018/02/2018Jan-Bone... · BoneAlbumin science summary January 2018 Page 4 7 Animal study 1. –3D

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

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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.


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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

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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


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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

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Animal models: a summary

Albumin coating resulted in much faster bone healing and stronger bone

than without albumin.


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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.

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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.


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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.


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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.


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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.


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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


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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)


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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.


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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


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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)

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Use of serum albumin coated allograft in bone replacementdynadental.com/app/uploads/2018/02/2018Jan-Bone... · BoneAlbumin science summary January 2018 Page 4 7 Animal study 1. –3D