University of Groningen Application of poly(trimethylene carbonate) and calcium phosphate composite biomaterials in oral and maxillofacial surgery Zeng, Ni

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University of Groningen

Application of poly(trimethylene carbonate) and calcium phosphate composite biomaterials in

oral and maxillofacial surgery

Zeng, Ni

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Publication date:

2017

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Zeng, N. (2017). Application of poly(trimethylene carbonate) and calcium phosphate composite

biomaterials in oral and maxillofacial surgery. Rijksuniversiteit Groningen.

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G E N E R A L I N T R O D U C T I O N A N D

A I M O F T H E T H E S I S

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INT ROD UC TI ON AN D A IM

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1 Tissues and organs in human bodies constantly renew themselves during their life time. Our

hair and nails keep growing and need to be cut regularly. We shed off dead skin every day.

Although not seen, epithelium lining our stomach and intestines is renewed and replaced

by new cells within a week(1). Despite the constant renewing of a human body, only a few

organs, including skin, liver and bone, are capable of self-regeneration when damaged, and

even such a regenerative capacity is within limitations. A simple bone fracture can heal by

rigid fixation of the fracture, but a large missing piece of skull or a severely resorbed alveolar

ridge, due to progressive periodontitis, do not come back to normal without augmentation.

Other needs for bone regeneration include reconstruction of bone defects caused by

trauma, tumors, infections, harvesting of bone grafts, and congenital abnormalities.

Facing diverse clinical challenges, a transition of bone substitute materials from space

holders to biologically active, custom-made biomaterials has been actively witted in oral

maxillofacial surgery(2).

Calcium phosphate bioceramics in forms of granules, scaffolds, coatings and injectable

cements have become increasingly popular bone substitutes for autologous bone grafts

in oral and maxillofacial surgery and orthopedics, because they chemically resemble

the inorganic components in natural bone and should possess osteoconductive capacities

to support bone ingrowth in the scaffolds(3). Hydroxyapatite (HA) has become a reference

material in the field of calcium phosphates for biomedical applications and other important

members of calcium phosphate bioceramics include beta-tricalcium phosphate(β-TCP)

and biphasic calcium phosphate (BCP), a mixture of HA and TCP. β-TCP is more commonly

used than α-TCP in biomedical applications because β-TCP has a lower solubility and thus

lower resorption kinetics(4). Various factors determine bioactivities of calcium phosphate

bioceramics, including sintering temperature, porosity and pore sizes, and these factors

are connected to each other. HA powders can withstand sintering temperatures of 1000 -

1200 °C and start becoming unstable at temperatures around 1250 - 1300 °C. Porous HA

bioceramics can be colonized by bone tissues, so interconnecting porous structures with

pore sizes larger than 100 μm is intentionally introduced in solid bioceramics(5). It takes

years for HA bioceramic scaffolds to get fully degraded in vivo and new bone formation is

seen occupying peripheral parts of the scaffolds(6). BCP bioceramic particles sintered at

a relatively low temperature (1150 °C) show a porous structure with interconnected pores

under the electron microscope (microporous), while BCP bioceramic particles sintered at

1300 °C do not show such a microporous structure(7). When implanted in a goat dorsal

muscle, BCP bioceramic particles sintered at 1150 °C induce new bone formation which

appears to be initiated at the surface of the particles. Such ectopic new bone formation

is not induced by BCP bioceramic granules sintered at 1300 °C. When implanted in defects

in goat iliac wings, the BCP bioceramic scaffolds with osteoinductive capacity lead to new

bone formation that is of significant large amount and deeper inside the scaffolds than

the BCP bioceramic scaffolds with only osteoconductive ability(7), stressing the importance

of osteoinductivity in regeneration of critical-sized bone defects. Although calcium

phosphate bioceramics have gained wide biomedical applications as fillers, coatings(8) or

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1 drug delivery carriers(9), their applications as scaffolds in load-bearing sites are still limited

by their inherent brittleness with a poor fatigue resistance(8).

One feasible solution to overcome the brittleness of calcium phosphate bioceramics is

to combine calcium phosphate bioceramics with polymers(10), since natural bone tissue is

a composite of HA and collagen fibers and mechanical properties of bone mainly depend on

the strength of the collagen fibers(11). A variety of polymers, of natural origin or synthetic,

have the potential to become part of composite biomaterials with calcium phosphate

bioceramics for bone regeneration. The most renowned choices include collagen,

poly(lactic acid), poly(glycolic acid), poly(ε-caprolactone) and copolymers of lactic acid/

glycolic acid/ ε-caprolactone(12). In our studies, we have used poly(trimethylene carbonate)

to incorporate calcium phosphate bioceramic particles because of its unique physical and

biocompatible properties.

Poly(trimethylene carbonate) (PTMC), an aliphatic polycarbonate, can be synthesized by

ring opening polymerization of 1,3-trimethylene carbonate (TMC) in different conditions

and using different catalysts, resulting in PTMC batches with different molecular

weight(13-15). Different molecular weights determine mechanical properties of PTMC biomaterials

and subsequently their biomedical applications. PTMC biomaterials undergo degradation

in a surface erosion process mediated by enzymes(16) both in vitro(17) and in vivo(18) and

the metabolites are not acidic in nature(19).Thanks to the degradation behavior of surface

erosion, PTMC of low molecular weight and TMC-based copolymers can be used as carriers

for controlled release of hydrophilic drugs(20, 21), growth factors(22, 23), anti-tumor

drugs(24, 25), and antibiotics(26). PTMC with a number average molecular weight above

200,000 (very high molecular weight)is synthesized under 130°C in vacuum for 3 days with

stannous octoate as a catalyst(27)and shows a Young’s modulus of 6 MPa, an elongation at

yield of 130%, and an elongation at break of 830%(28). With a glass transition temperature

of around -17°C, the amorphous PTMC polymer is in its rubbery state at room temperature

and is flexible(13, 27). Therefore, PTMC biomaterials with very high molecular weight display

favorable properties, combining high flexibility with high tensile strength, which are suitable

for tissue engineering purposes but not in load bearing situations. Besides, TMC monomers

are commonly used to form copolymers with lactic acid, glycolic acid, ε-caprolactone, or

other monomers, imparting elasticity to these copolymers and tuning their degradation

behaviors. Copolymers made of glycolic acid and TMC have been successfully used as synthetic

degradable monofilament sutures with high tensile strength (Maxon

TM

_{)(29). In soft tissue}

engineering, PTMC and copolymers of TMC with lactic acid, glycolic acid, ε-caprolactone,

or other monomers have been applied for regeneration of damaged nerve tissue(30, 31),

myocardial tissue(32, 33) or blood vessels(34-37). The application of TMC-based polymers in

hard tissue regeneration is less well investigated. PTMC microspheres with high molecular

weight are used to formulate calcium phosphate cements (CPC) with an initial setting time

of around two to three minutes and a compression strength of 15-24 MPa(38). In repairing

defects in jawbones, membranes made of very-high-molecular-weight PTMC have been

shown suitable to be used as barrier membranes for guided bone regeneration(39). Besides,

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1 such PTMC membranes have also been shown feasible to be used in bone augmentation

procedures with bone grafts(40).

A I M O F T H E T H E S I S

Aim of the present research is to evaluate applications of composite biomaterials composed

of poly(trimethylene carbonate) (PTMC) and calcium phosphate bioceramic particles

in the forms of membranes and porous scaffolds for indications in the field of oral and

maxillofacial surgery. The clinical circumstances to which the composite biomaterials should

be applied include guided bone regeneration, bone augmentation with block autologous

bone grafts for a proper placement of dental implants and reconstruction of critical sized

cranial bone defects.

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1 R E F E R E N C E S

1. ELSEVIER PO, FINAL SC. Tissue Renewal, Regeneration, and Repair.

2. Kolk A, Handschel J, Drescher W, Rothamel

D, Kloss F, Blessmann M, et al. Current trends and future perspectives of bone substitute materials – From space holders to innovative biomaterials. Journal of Cranio-Maxillofacial Surgery. 2012 12;40(8):706-18.

3. Tay BK, Patel VV, Bradford DS. Calcium sulfate-

and calcium phosphate-based bone substitutes. Mimicry of the mineral phase of bone. Orthop Clin North Am. 1999 Oct;30(4):615-23.

4. Dorozhkin SV. Bioceramics

of calcium orthophosphates. Biomaterials. 2010 3;31(7):1465-85.

5. Omae H, Mochizuki Y, Yokoya S, Adachi N,

Ochi M. Effects of interconnecting porous structure of hydroxyapatite ceramics on interface between grafted tendon and ceramics. Journal of Biomedical Materials Research Part A. 2006;79A(2):329-37.

6. van Eeden SP, Ripamonti U. Bone

differentiation in porous hydroxyapatite in baboons is regulated by the geometry of the substratum: implications for reconstructive craniofacial surgery. Plast Reconstr Surg. 1994 Apr;93(5):959-66.

7. Habibovic P, Yuan H, van den Doel M,

Sees TM, van Blitterswijk CA, de Groot K. Relevance of Osteoinductive Biomaterials in Critical-Sized Orthotopic Defect. Journal of Orthopaedic Research. 2006;24(5):867-76.

8. Salinas AJ, Vallet-Regí M. Evolution of

Ceramics with Medical Applications. Zeitschrift für anorganische und allgemeine Chemie. 2007;633(11-12):1762-73.

9. Bose S, Tarafder S. Calcium phosphate ceramic

systems in growth factor and drug delivery for bone tissue engineering: A review. Acta Biomaterialia. 2012 4;8(4):1401-21.

10. Rezwan K, Chen QZ, Blaker JJ, Boccaccini AR. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials. 2006 Jun;27(18):3413-31.

11. Dorozhkin SV. Calcium orthophosphate-based biocomposites and hybrid biomaterials. J Mater Sci. 2009;44(9):2343-87.

12. Dorozhkin SV. Calcium Orthophosphate-Containing Biocomposites and Hybrid Biomaterials for Biomedical Applications. J Funct Biomater. 2015 Aug 7;6(3):708-832. 13. Zhu KJ, Hendren RW, Jensen K, Pitt CG.

Synthesis, properties, and biodegradation of poly(1,3-trimethylene carbonate). Macromolecules. 1991 04/01; 2012/04;24(8):1736-40.

14. Bisht KS, Svirkin YY, Henderson LA, Gross RA, Kaplan DL, Swift G. Lipase-Catalyzed Ring-Opening Polymerization of Trimethylene Carbonate. Macromolecules. 1997 12/01; 2012/04;30(25):7735-42.

15. Matsumura S, Tsukada K, Toshima K. Novel lipase-catalyzed ring-opening copolymerization of lactide and trimethylene carbonate forming poly(ester carbonate)s. Int J Biol Macromol. 1999 6;25(1–3):161-7. 16. Zhang Z, Zou S, Vancso GJ, Grijpma

DW, Feijen J. Enzymatic surface erosion of poly(trimethylene carbonate) films studied by atomic force microscopy. Biomacromolecules. 2005 Nov-Dec;6(6):3404-9. 17. Pêgo AP, Poot AA, Grijpma DW, Feijen J. In

Vitro Degradation of Trimethylene Carbonate Based (Co)polymers. Macromolecular Bioscience. 2002;2(9):411-9.

18. Pêgo AP, Van Luyn MJA, Brouwer LA, van Wachem PB, Poot AA, Grijpma DW, et al. In vivo behavior of poly(1,3-trimethylene carbonate) and copolymers of 1,3-trimethylene carbonate with D,L-lactide or ε-caprolactone: Degradation and tissue response. Journal of Biomedical Materials Research Part A. 2003;67A(3):1044-54. 19. Zhang Z, Kuijer R, Bulstra SK, Grijpma DW,

Feijen J. The in vivo and in vitro degradation behavior of poly(trimethylene carbonate). Biomaterials. 2006 3;27(9):1741-8.

20. Zhang Z, Grijpma DW, Feijen J. Trimethylene carbonate-based polymers for controlled drug delivery applications. J Controlled Release. 2006 11/28;116(2):e28-9.

21. Zhang Z, Grijpma DW, Feijen J. Poly(trimethylene carbonate) and monomethoxy poly(ethylene glycol)-block-poly(trimethylene carbonate)

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1

nanoparticles for the controlled

release of dexamethasone. J Controlled Release. 2006 4/10;111(3):263-70.

22. Chapanian R, Amsden BG. Combined and sequential delivery of bioactive VEGF165 and HGF from poly(trimethylene carbonate) based photo-cross-linked elastomers. J Controlled Release. 2010 4/2;143(1):53-63. 23. Amsden BG, Timbart L, Marecak D,

Chapanian R, Tse MY, Pang SC. VEGF-induced angiogenesis following localized delivery via injectable, low viscosity poly(trimethylene carbonate). J Controlled Release. 2010 7/14;145(2):109-15.

24. Sanson C, Schatz C, Le Meins J, Soum A, Thévenot J, Garanger E, et al. A simple method to achieve high doxorubicin loading in biodegradable polymersomes. J Controlled Release. 2010 11/1;147(3):428-35. 25. Jelonek K, Kasperczyk J, Li S, Dobrzynski

P, Jarzabek B. Controlled poly(l-lactide-co-trimethylene carbonate) delivery system of cyclosporine A and rapamycine – the effect of copolymer chain microstructure on drug release rate. Int J Pharm. 2011 7/29;414(1–2):203-9. 26. Neut D, Kluin OS, Crielaard BJ, van

der Mei HC, Busscher HJ, Grijpma DW. A biodegradable antibiotic delivery system based on poly-(trimethylene carbonate) for the treatment of osteomyelitis. Acta Orthop. 2009 Oct;80(5):514-9.

27. Pego AP, Poot AA, Grijpma DW, Feijen J. Copolymers of trimethylene carbonate and epsilon-caprolactone for porous nerve guides: synthesis and properties. J Biomater Sci Polym Ed. 2001;12(1):35-53.

28. Pego AP, Poot AA, Grijpma DW, Feijen J. Physical properties of high molecular weight 1,3-trimethylene carbonate and D,L-lactide copolymers. J Mater Sci Mater Med. 2003 Sep;14(9):767-73.

29. Tajirian AL, Goldberg DJ. A review of sutures and other skin closure materials. J Cosmet Laser Ther. 2010 Dec;12(6):296-302. 30. Pêgo AP, Vleggeert-Lankamp CLAM, Deenen

M, Lakke EAJF, Grijpma DW, Poot AA, et al. Adhesion and growth of human Schwann cells on trimethylene carbonate (co)

polymers. Journal of Biomedical Materials Research Part A. 2003;67A(3):876-85. 31. Lietz M, Ullrich A, Schulte-Eversum C,

Oberhoffner S, Fricke C, Müller HW, et al. Physical and biological performance of a novel block copolymer nerve guide. Biotechnol Bioeng. 2006;93(1):99-109. 32. Pego AP, Siebum B, Van Luyn MJ, Gallego y

Van Seijen XJ, Poot AA, Grijpma DW, et al. Preparation of degradable porous structures based on 1,3-trimethylene carbonate and D,L-lactide (co)polymers for heart tissue engineering. Tissue Eng. 2003 Oct;9(5):981-94. 33. Bat E, Harmsen MC, Plantinga JA, van Luyn MJA, Feijen J, Grijpma DW. Flexible scaffolds based on poly(trimethylene carbonate) networks for cardiac tissue engineering. J Controlled Release. 2010 11/20;148(1):e74-6. 34. Song Y, Kamphuis MMJ, Zhang Z, Sterk

LMT, Vermes I, Poot AA, et al. Flexible and elastic porous poly(trimethylene carbonate) structures for use in vascular tissue engineering. Acta Biomaterialia. 2010 4;6(4):1269-77. 35. Song Y, Wennink JWH, Kamphuis MMJ, Vermes I,

Poot AA, Feijen J, et al. Effective seeding of smooth muscle cells into tubular poly(trimethylene carbonate) scaffolds for vascular tissue engineering. Journal of Biomedical Materials Research Part A. 2010;95A(2):440-6.

36. Song Y, Wennink JW, Poot AA, Vermes I, Feijen J, Grijpma DW. Evaluation of tubular poly(trimethylene carbonate) tissue engineering scaffolds in a circulating pulsatile flow system. Int J Artif Organs. 2011 Feb;34(2):161-71.

37. Buttafoco L, Boks NP, Engbers-Buijtenhuijs P, Grijpma DW, Poot AA, Dijkstra PJ, et al. Porous hybrid structures based on P(DLLA-co-TMC) and collagen for tissue engineering of small-diameter blood vessels. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2006;79B(2):425-34. 38. Habraken WJ, Zhang Z, Wolke JG, Grijpma

DW, Mikos AG, Feijen J, et al. Introduction of enzymatically degradable poly(trimethylene carbonate) microspheres into an injectable calcium phosphate cement. Biomaterials. 2008 Jun;29(16):2464-76.

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39. van Leeuwen AC, Huddleston Slater JJR, Gielkens PFM, de Jong JR, Grijpma DW, Bos RRM.

Guided bone regeneration in rat mandibular defects using resorbable poly(trimethylene carbonate) barrier membranes. Acta Biomaterialia. 2012 4;8(4):1422-9.

40. Zeng N, van Leeuwen A, Yuan H, Bos RRM, Grijpma DW, Kuijer R. Evaluation of novel resorbable membranes for bone augmentation in a rat model. Clin Oral Implants Res. 2014:e8-e14.

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