Pregled raspoloživih biomaterijala pogodnih za brzu izradu prototipova

1. Pregled raspoloživih biomaterijala pogodnih za brzu izradu prototipova Mr Jelena Milovanovic

2. Research papers • Scaffold development using 3D printing with a starch based polymer (2002), C.X/F/ Lam, X.M. Mo, S.H. Teoh, D.W. Hutmacher. • Evaluation of the improvement RP powder stereo shaped techniques to directly solidified modeling of biochemistry composite powder material(2006), Shung Ping Sun, Yi Jiun Chou, W.L.Yao, Yu Fu Chen • Development of a new calcium phosphate power binder system for the 3D printing of patient specific implants, (2007), Alaadien Khalyfa, Sebastian Vogt… • Biocompatibility of cheramic scraffolds for bone replacement made by 3D printing, (2005), B. Leukers, H. Gulkan, S.H. Irsen, S. Milz, …

3. Research papers • Towards bone replacement materials from calcium phosphates via rapid prototyping and ceramic gelcasting, (2005), A. Woesz, M Rumpler, J stampfl… • Levofloxacin implants with predefined microstructure fabricated by three dimensional printing technique, (2007), Weidong Huang, QixinZheng… • Materials for biomedical application, N.K.Vail, L.D. Swain, W.C. Fox… • The fabrication of biocompatible and bioactive implants Bio CAD modeling and its applications in computer aided tissue engineering, (2005), W. Sun, B. Starly, J. Nam, A. Darling • Application of micro CT and computation modeling in bone tissue engineering, (2005), Ho Saey Tuan, Dietmar W. Hutmacher. • Custom made implants, (2004), Lara Kristin Lentini

4. STUDY 1-PlastiBone / Advanced Ceramic Research • The Office of Naval Research and Advanced Ceramics Research partnered to develop a new type of artificial bone capable of supporting new bone growth and porous enough to be absorbed by the body. • In current absorbable orthopedic implant materials, the affected bone is in danger of becoming too weak before substantial mass loss of the implant. • With use of current materials such as copolymerized polylactic and polyglycolic acids (PLA/PGA) as bone fillers, patients may find bones are too weak to carry any load long before significant amounts of bone have grown to replace the eroded prosthesis.

5. PlastiBone / Advanced Ceramic Research • An alternative to current implant technologies is a two-stage implant material that is both load bearing and osteoconductive. • Code from MRI or CT imaging scans would be passed to RP machines which would make the damaged segment from a polymer coated with tricalcium phosphate.The ceramic coated biocompatible plastic would in turn be broken down over the next 18 months by the body after bone cells had filled the pores in the ceramic. All that would remain of the implant would be some of the original polymer core encased in sturdy bone tissue. .

6. 1. Scanning the damage The first step is to create a CT or MRI scan of the damaged limb and its healthy opposite. The data must undergo conversion to the type of code that the rapid-prototyping machine uses—an intermediate step that Wohlers envisions will be simplified or eliminated in the future.

7. 2. Designing the plasti-bone replacement A mirror image of the data from the opposite limb is used to match the missing, diseased, or shattered section of bone with precise accuracy. This digital blueprint determines the exact dimensions of the graft that the RP machine will produce.

8. 3. Prototyping the bone fragment After the precise shape of the replacement is determined, the data is sent to the 3-D extrusion machine, which “prints” the plastic graft—later covered with a layer of ceramic material—at a rate of about an hour per half inch.

9. 4. The prototyped replacement The graft’s specialized plastic material is its most innovative feature. “The biggest issue in rapid prototyping biomedical products is making functional products that can withstand conditions inside the body,”. “We had to develop a hybrid approach—one that could withstand the im-plant conditions and also stay in the body long enough so that enough bone mass could be built up inside the implant.” The graft is made of a substance “very similar to the material used in milk jugs,” “then coated with a thin layer of tri-calcium phosphate, which is similar to our bone.”

10. 5. Implanting the replacement The Plasti-Bone is surgically implanted, and the ends are attached to the remaining healthy bone. An outer cast is applied to keep the graft and bone properly aligned during the healing process.

11. 6. New bone growth During the next eight weeks the Plasti-Bone functions like a scaffold to support the patient’s muscle while healthy bone cells attach to the tri-calcium phosphate layer. As the cells grow back through the porous graft, they “eat” the scaffold, leaving nothing but the patient’s own healthy living bone.

12. New bone growth

13. Biomaterials for 3D printing-Study 1 • This study apply the RP powder stereo-shaped techniques and using standard biochemistry materials to discuss how biochemistry composite powder material can directly be solidified by using rapid prototyping machines to become bone-filling graft for missing bone on clinical surgery. • As for the materials of implants, the research using commercialized composite powder materials.

14. Bone graft material • According to the modification of the RP equipment, which the research is used, can be upgrade the solidification quality of bone graft material. • Bone replenishment is formed by mixing PMMA (polymethylmethacrylate) and fine granule of bone cement • The ready bone cement is a compound consisting of 90 % ofpolymethylmetacrylate, (PMMA), the rest are mainly crystals of barium sulfate or Zirconium oxide . • Its strength is a little weaker than hand-pressed mixed bone powder replenishment, but it still fit the average bone strength that the body requires.

15. Bone graft material • According to each different body part, the required strength will be different. • As for femur, it bears the strength of a half of the upper body. • Materials with the compression larger than 60 MPa of bone strength or above in average,and the bending strength of 3 points are larger than 15 MPa or above in average all can be use as a bone replacement.

16. The improvements of Z402 spray head andreplace by ABS material. The improvement of PMMA glue supply unit (directly providing glue to spray head).

17. 3D printing machine modification

18. The aim of the study • This study is in Zcorp402 shower nozzle structure improvement that change the part of the shower nozzle of the first half into the material of ABS. • It can avoid the dissolving to the shower nozzle of glue, and want to make the glue not pass the mechanical pipeline that packed the glue by the first half of the shower nozzle directly • It is commercial prescription in glue, and it will make PMMA shaping and solidify after joining function. • This kind of glue belongs to the high polymer material. • This method can prevent the glue from touching the part within machinery.

19. Results • The bone replenishment developed in the research are made by rapid prototyping machine, therefore the strength is a little weaker than the strength of replenishment made in traditional way. • The mechanical properties and related characteristics of the replenishment made by this process can all satisfy the need of artificial bone implant.

20. STUDY 2 • Three-dimensional printing (3DP) technique was used to fabricate scaffolds in combination with natural polymer and water based binder. • In this study, a unique blend of starch-based polymer powders (cornstarch, dextran and gelatin) was developed for the 3DP process.

21. Materials • The commercial 3D printer(Z402) was used for the study • The properties of used biomaterial would require that it operates well within the parameters and constraints of the printer. • A three powder blend was formulated for the experiments. • It consisted of 50wt.% cornstarch(Max’s Holland; 10µm), 30wt.% dextran(Sigma, USA >100µm) and 20wt.% gelatin(Nitta Gelatin, Japan; >100µm). • Starch is a polysaccharide produced by higher plants as energy storage and is composed of two polymers of d-glucose:amylose and amylpectin. • Amylose is a lightly branched polymer, while amylopectin is highly branched with overall tree like structure. • Dextran is polysaccharide secreted by certain strains of bacteria and slimes. • Gelatin is made from naturally occurring collagen in animals. It is polypeptide and contains 18 different amino acids. • Distilled water was used as the binder in combination with blue dye to ease processing and investigations

22. Results • 3D scaffolds created by a new blend of materials through 3DP were achievable. • However biocompability of set of materals used needs to be studied in the future.

23. STUDY 3 • Used material: spaydried Hydroxyapatite(HA)-granulate named V5 • Besides the main component HA it contains polymeric additives to improve bonding and flowability • As a binder we used Schelofix which consists of water soluble polymeric compounds • Materials were obtained from the Friedrich-Baur-Institute (FBI, Germany) • For printing, the binder powder was dissolved in water to yield a 14% solution (ww)

24. Results • This material does not exert any cytotoxicity after sintering and that adhering cells proliferate adequately. • The flexibility of the 3DP process offers possibility to realize more complex stuctures than described here. • 3D printing process based on HA powder is promising for producting patient specific implants for bone repair with interconnective structures.

25. STUDY 4 • Used material: developed a powder mixture comprising tetracalcium phosphate(TTCP) as reactive component and β-tricalcium phosphate (β –TCP) or calcium sulfate as biodegradable fillers, • Conventional 3DP eqipment can be used to print this material with an aqueous citric acid solution as binder. • No organic solvents are needed in the printing process. • Because of their chemical and structural similarities to the inorganic phase of human bone, hydroxyapatite(HA) and other calcium phosphates like α-or β-tricalcium phosphate (α-or β-TCP) show an excellent biocompatibility.

26. Results • Based of the known biocompatibility of the used components, patient specific implants or scaffolds fabricated by this technology represent promising biomaterials for bone reconstruction even in load bearing areas dominated by compressive stresses.

27. STUDY 5 - Biphasic Calcium Phosphate/Poly-Dl-Lactide-Co-Glycolide Composite Biomaterial as Bone Substitute • Prof dr Dragan Uskoković i Prof. dr Nenad Ignjatović • Sinteza nanokristalnih i nanostrukturnih kalcijum fosfata i kompozita za rekonstrukciju koštanog tkiva predstavlja osnovno polje istraživanja dela grupe za nove materijale i procese Instituta tehničkih nauka Srpske akademije nauka i umetnosti (ITN SANU) u Beogradu.

28. Ovim materijalom i određenim biokompatibilnim polimerima je sintetisan kompozitni biomaterijal koji se s pravom može nazvati „VEŠTAČKA KOST“. Mada je sintetisana veštačkim putem, ona je ne samo po hemijskom sastavu nego i po strukturi gotovo ista kao prirodna kost, a poseduje i ista mehanička svojstva, poroznost itd. Veštačka kost

29. Materijal • Koncept ovog biomaterijala i implanata koji su od njega napravljeni sasvim je nov i razlikuje se od svih ranije poznatih. Naime, nakon implantacije ovaj „pametni material“, jednostavno rečeno, „oživi“, prilagođava se potrebama organizma i njegovom metabolizmu i na kraju nestaje (umire) a na njegovo mesto dolazi novoformirano tkivo. • Ovaj biomaterijal se sastoji od bioneresorbilne i organizmu potrebne komponente (hidroksiapatita i trikalcijum fosfata) i bioresorbilne polimerne komponente. Vremenom se polimer resorbuje i nestaje a produkti njegove razgradnje – voda i ugljendioksid – apsolutno su neštetni za bilo koji organizam. Polimer nestaje istom brzinom kojom se formira novo tkivo organizma, tako da na kraju procesa reparacije mesto polimera zauzima novo tkivo koje je sam organizam stvorio. Iz tih razloga, proliferacija tkiva kroz implant je potpuna.

30. Materijal- mogućnost primene • Kompozitni biomaterijali u smeši sa faktorima rasta formiraju novu grupu pametnih biomaterijala koji poseduju ne samo konektivna svojstva nego i induktivna, tako da mogu da ubrzavaju proces rekonstrukcije i oporavka. Proces rekonstrukcije može se ubrzati unošenjem odredjenih faktora rasta u sam materijal. Ako srastanje određenog preloma traje dva meseca, sa faktorima rasta taj proces se može gotovo dvostruko skratiti. To omogućava kvalitetniji način života svakom pacijentu tokom i nakon zahvata. Sam proces sinteze ovog kompozita omogućava projektovanje hemijskih, mehaničkih ali i bioloških svojstava, što proširuje mogućnost primene ovog postupka • Osnovna polja istraživanja su fokusirana u okviru sledećih oblasti: • Prah, blokovi i različite 3D komponente bez ograničenja dimenzija, izrađene od kompozitnog biomaterijala CP/bioresorbilni polimer ( BioHapel ) sa i bez kolagena za reparaciju različiti koštanih defekata

31. Materijal- mogućnost primene • Nano kompozitni biomaterijali u formi praha ili gela. Čestice CP su obložene biokompatibilnim polimerom i veličina su do 50 nm. Ovakve čestice su idealne za dobijanje gelova ili pasta koji omogućavaju rekonstrukciju injektiranjem u defekt. • Nano sfere bioresorbilnih polimera kao nosači aktivnih farmaceutskih agenasa za upotrebu u ciljanom i kontrolisanom lečenju šireg spektra benignih i malignih oboljenja. • Veliki značaj sastoji se u tome što su svi kompozitni biomaterijali koji su sintetisani u laboratoriji ispitani na velikom broju eksperimentalnih životinja (na medicinskom i stomatološkom fakultetu), a klinička istraživanja su u toku. Širok spektar različitih vrsta implanata je sintetisan i dizajniran u laboratoriji a takođe je u potpunosti osvojena tehnologija za proizvodnju malih serija različitih vrsta implanata koji se široko mogu koristiti u ortopediji, maksilofacijalnoj hirurgiji, otorinolaringologiji itd.

32. Materijal- istraživanja • U istraživanjima izvedenim na velikom uzorku eksperimentalnih životinja dr Zorica Ajduković sa Stomatološkog fakulteta u Nišu potvrdila je aplikativne vrednosti ovih materijala. • Rešavanje problema deficita koštanog tkiva izazvanog uznapredovalom resorpcijom alveolarne kosti u sklopu sistemske osteoporoze, • Prof dr Vitomir Konstantinović sa Stomatološkog fakulteta u Beogradu ispitivao je mogućnosti primene ovih biomaterijala u formi punilaca...

33. Dosadašnja istraživanja • Dosadašnja istraživanja dala su izvanredne rezultate kako u domenu naučnih istraživanja tako i u krajnje pozitivnom biološkom odgovoru organizma na implantaciju ovog biomaterijala potvrđenu u nizu kliničkih istraživanja. • Najveći problem koji on ističe jeste nemogućnost prenošenja ovih znanja i proizvoda domaćim institucijama i organizacijama.

34. Reference • [1] N. Ignjatovic. P. Ninkov, Z. Ajdukovic, D. Vasiljevic-Radovic, D. Uskokovic, "Biphasic Calcium Phosphate/Poly-Dl-Lactide-Co-Glycolide Composite Biomaterial as Bone Substitute", Journal of the European Ceramic Society 27 (2007) 1589–1594 • [2] N. Ignjatovic, P. Ninkov, Z. Ajdukovic, V. Konstantinovic, D. Uskokovic, Biphasic Calcium Phosphate/Poly-(DL-Lactide-co-Glycolide) Biocomposite as Filler and Blocks for Reparation of Bone Tissue, Materials Science Forum 494 (2005) 519–524 • [3] N. Ignjatovic, Z. Ajdukovic, D. Uskokovic, New biocomposite calciumphosphate/poly-DL-lactide-co-glicolide/biostimulatite agens filler for reconstruction of bone tissue changed by osteoporosis", Journal of Materials Sciences: Materials in Medicine, 16 (2005) 621–626 • [4] Z. Ajdukovic, N. Ignjatovic, D. Petrovic, D. Uskokovic, "Substitution of Osteoporotic Alveolar Bone by Biphasic Calciumphosphate/Poly-Dl-Lactide-Co-Glycolide Biomaterials", Journal of Biomaterials Application 21 (2007) 317–328 • [5] R. Zivkovic, Lj. Kesic, D. Mihailovic, N. Ignjatovic, D. Uskokovic, Investigation of HeNe laser therapy influence on BCP/PLGA osseointegration - Experimental study, Facta Universitatis, Series: Medicine and Biology , 13 (2006) 109–113

35. HVALA NA PAŽNJI !!!