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Synthesis, characterization of calcium phosphates/polyurethane

composites for weight-bearing implants

Toshitaka Yoshii,1,2,3,4 Jerald E. Dumas,2,3 Atsushi Okawa,4 Dan M. Spengler,1 Scott A. Guelcher2,3

1

Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee 37232-87742Center for Bone Biology, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, Tennessee 37232-05753Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 372354Section of Orthopaedic and Spinal Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan

Received 17 December 2010; revised 13 June 2011; accepted 16 June 2011

Published online 26 September 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.b.31917

Abstract: Calcium phosphate (CaP)/polymer composites have

been studied as an alternative graft material for the treatment

of bone defects. In this study, lysine-triisocyanate-based poly-

urethane (PUR) composites were synthesized from both hy-

droxyapatite (HA) and b-tricalcium phosphate (TCP) to reduce

the brittleness of CaP and increase the bioactivity of the poly-

mer. The mechanical properties and in vitro cellular responsewere investigated for both HA/PUR and TCP/PUR composites.

The composites were implanted in femoral defects in rats,

and in vivo bioactivity was evaluated by X-rays, micro-com-

puted tomography (lCT), and histological sections. In biome-

chanical testing, PUR improved the mechanical properties of

the CaP, thus rendering it potentially suitable for weight-bear-

ing applications. In vitro cell culture studies showed that CaP/

PUR composites are biocompatible, with b-TCP enhancing

the cell viability and proliferation relative to HA. CaP/PUR

composites also supported the differentiation of osteoblastic

cells on the materials. When implanted in rat femoral defects,

the CaP/PUR composites were biocompatible and osteocon-

ductive with no adverse inflammatory response, as evi-

denced by X-rays, lCT images, and histological sections.

Additionally, a histological examination showed evidence ofcellular infiltration and appositional remodeling. These

results suggest that CaP/PUR composites could be potentially

useful biomaterials for weight-bearing orthopaedic implants.

VC 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Bio-

mater 100B: 3240, 2012.

Key Words: polyurethane, calcium phosphate, weight-bearing,

osteoconductive, resorbable

How to cite this article: Yoshii T, Dumas JE, Okawa A, Spengler DM, Guelcher SA. 2012. Synthesis, characterization of calcium

phosphates/polyurethane composites for weight-bearing implants. J Biomed Mater Res Part B 2012:100B:3240.

INTRODUCTION

Calcium phosphates (CaP) have been extensively investi-

gated for treating osseous defects. Hydroxyapatite (HA) and

tricalcium phosphate (TCP) have been shown to be osteo-

conductive.1 The composition of bone is approximately 70%

mineral content, which is primarily HA.2 Thus because of its

natural presence in bone, synthetic HA is an attractive bone

substitute. HA is prepared from the hydrothermal conver-

sion of bone or naturally occurring coralline apatite, and it

can be synthesized with variable porosity.3 TCP is a biocom-

patible and bioactive ceramic that has been demonstrated

to bond to bone directly.

4,5

Whereas HA bone cements ex-hibit compressive strengths in the range of 450 MPa,6,7

TCP has a significantly lower strength than HA.3 Despite

their favorable biocompatibility and osteoconductivity, both

HA and TCP are subject to brittle fracture and graft migra-

tion, potentially requiring additional surgeries for repair or

removal.3,8,9

CaP/polymer composites have been synthesized to

reduce the brittleness of CaP as well as to increase the bio-

activity of the polymer.8 Multiple polymeric systems have

been used to prepare CaP composites with varying poros-

ities and compositions.10 HA/chitosan/PLA composites syn-

thesized using in situ precipitation with 5080 wt % HA

exhibit compressive elastic modulus and strength values in

the range of 416857 MPa and 166256 MPa, respec-

tively.11 HA/PLA composites synthesized using solvent cast-

ing at lower HA contents (3040 wt %) can have a bendingstrength and modulus as high as 269 MPA and 7.6 GPa,

respectively.1215 These composites remodeled almost com-

pletely when implanted as intramedullary rods in the distal

femur of rabbits after five to seven years.12

Correspondence to: S. A. Guelcher; e-mail: [email protected]

Contract grant sponsor: Center for Military Biomaterials Research; contract grant numbers: USAMRAA/DOD Award #W81XWH-04, Subaward

#2109

Contract grant sponsor: National Science Foundation CAREER Award; contract grant number: DMR-0847711

Contract grant sponsor: Vanderbilt University School of Engineering

32 VC 2011 WILEY PERIODICALS, INC.


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samples. Calcein AM dye is retained within live cells, imparting

green fluorescence (excitation/emission: 495/515 nm). Cell

proliferation was assessed qualitatively by fluorescent images

acquired with an Olympus DP71 camera attached to a fluores-

cent microscope (Olympus CKX41, U-RFLT50). Osteoblastic

cell proliferation on CaP/PUR composites was quantitatively

evaluated using PicoGreen assays (n 4). After the cells were

removed from the discs using 0.25% trypsin and 1 mMethyle-nediaminetetraacetic acid (EDTA, Invitrogen), DNA content

was measured using the Quant-iT PicoGreen dsDNA assay kit

(Invitrogen-Molecular Probes) according to the manufacturers

instructions. The fluorescence intensity was measured at exci-

tation and emission wavelengths of 495 and 515 nm2.

The in vitro osteogenic differentiation of osteoblastic cells

cultured on CaP/PUR composites was evaluated (n 4). A

cell number of 5 104 was seeded on CaP/PUR composites.

After confluence, the cell-seeded scaffolds were cultured with

osteogenic medium containing 2.5% FBS, 10 mM b-glycero-

phosphate (Sigma-Aldrich), and 100 lg/mL ascorbic acid

phosphate (Wako, Osaka, Japan) for 1, 4, and 7 days. The cells

were removed from the CaP/PUR discs, washed with PBS,and lysed with 0.1% Triton X-100. The cells were then sub-

jected to three freeze/thaw cycles and sonication. The lysates

(20 lL) were added to 100 lL of substrate buffer (2 mg/mL

disodium p-nitrophenylphosphate hexahydrate and 0.75M 2-

amino-2-methyl-1-propanol). After incubation of the mixtures

at 37C for 30 min, absorbance at 405 nm was measured.

Alkaline phosphatase (ALP) activity was determined from a

standard curve generated by employing the reaction of a p-

nitrophenol solution. ALP activity was normalized by DNA

content determined using the PicoGreen assay. The Students

t test and one-way ANOVA with the Bonferroni correction

was performed for statistical comparison (P< 0.05).

In vivo rat study

All surgical procedures were reviewed and approved by the

Institutional Animal Care and Use Committee. Male Sprague-

Dawley rats (Harlan Labs) aged 8 weeks (200250 g) were

used for this study. A mono-cortical plug bone defect with a

diameter of 3 mm was created in the distal region of the fe-

mur diaphysis, and a cylindrical CaP/PUR composite (3 5

mm2) was implanted into the defect. After 4 weeks, the rats

were sacrificed and the femurs removed and fixed in 10%

phosphate-buffered formalin.

lCT analysis

Radiological analysis of the defect in the distal femur at week

4 was performed using a Scanco lCT40 (SCANCO Medical) at

a voxel size of 24 lm. The X-ray source settings were 55 kVp

and 145 mA with an integration time of 300 ms.

Histology

Rat bones were decalcified with 10% EDTA, dehydrated,

embedded in paraffin, and sectioned at 5 lm thickness. The

coronal slice sections were stained with hematoxylin and

eosin (H&E). The specimens were examined with light mi-

croscopy. Tartrate resistant acid phosphastase (TRAP) stain-

ing was used to confirm the presence of osteoclasts.

RESULTS

Mechanical properties, particle size, in vitro

degradation

Figure 1 summarizes the compressive modulus and strength

values for the CaP/PUR composites, which ranged from 2.5 to

3.6 GPa and 59.6 to 87.0 MPa, respectively. HA/PUR composites

exhibited significantly greater compressive modulus and

strength values than the TCP/PUR composites at both examined

filler contents. However, the volume fraction of filler did not

have a significant effect on compressive strength for either type

of filler. Increasing the filler content for the b-TCP groups had

no significant effect on the modulus unlike the effects seen for

the HA group, where the modulus increased with filler content.

SEM images of the CaP/PUR composites are shown inFigure 2. After compression molding, the particle size was

reduced from 50150 lm to


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of live cells at day 5 increased relative to day 2 on both HA/

PUR and TCP/PUR composites, which suggests the biocom-

patibility of CaP/PUR composites. A quantitative analysis

with a PicoGreen assay also showed that the amount of cellu-

lar DNA significantly increased at day 5 on both HA/PUR and

FIGURE 3. In vitro degradation of PUR/HA, PUR/TCP composites and

Control (PUR). *p< 0.05, compared with PUR/TCP.

FIGURE 2. SEM images of HA70, HA79, TCP70, and TCP79 composites. The bottom panels show higher magnification images of the HA79

composites.

FIGURE 4. Proliferation of osteoblastic cells seeded on the surface of

PUR/HA and PUR/TCP composites. The cells were stained by calcein

at days 2 and 5. The bars: 250 lm. [Color figure can be viewed in the

online issue, which is available at wileyonlinelibrary.com.]

ORIGINAL RESEARCH REPORT

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH B: APPLIED BIOMATERIALS

|JAN 2012 VOL 100B, ISSUE 1 35


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TCP/PUR composites (79 wt %) (Figure 5). The rate of pro-

liferation on the TCP/PUR composites was greater than the

rate of cell growth on HA/PUR composites.ALP activity of the cells seeded on CaP/PUR composites

(79 wt %) significantly increased when cultured with osteo-

genic medium (Figure 6). ALP activity showed time-depend-

ent increases in both HA/PUR and TCP/PUR composites,

suggesting that the cells can differentiate on the surface ofthe composites. There was no significant difference in ALP

activity between HA/PUR and TCP/PUR composites.

FIGURE 5. DNA amount of osteoblastic cells cultured on PUR/HA and

PUR/TCP composites surfaces at days 2 and 5. * p< 0.05.

FIGURE 6. Osteogenic differentiation of osteoblastic cells seeded on

PUR/HA and PUR/TCP composites. ALP activity was measured at days

1, 4, 7 after culture on the composites with osteogenic supplements

(OS). *p< 0.05, compared with day 1.

FIGURE 7. Micro CT of PUR/HA and PUR/TCP composites at week 4. A: Coronal view. B: Axial view. Scale bars: 500 lm.

36 YOSHII ET AL. CALCIUM PHOSPHATES/POLYURETHANE FOR WEIGHT-BEARING IMPLANTS


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lCT analysis

lCT images from the extracted femurs at week 4 (Figure 7)

showed new bone formation around both HA/PUR and

TCP/PUR composites (79 wt %). The material shape

became irregular at the boundary between the implant and

newly formed bone in the lCT images. These findings show

that the composites are osteoconductive and support appo-

sitional bone growth.

Histology

Histological sections of the implanted CaP/PUR composites

(79 wt %) (Figure 8) showed extensive bone matrix

FIGURE 8. Histological pictures (HE staining) of PUR/HA and PUR/TCP composites at week 4. A: P, proximal; D, distal; I, implants. The bars: 500

lm. B: High magnification. The white arrows: cell infiltration to the scaffolds. The black arrows: New bone formation. Scale bars: 100 lm.

FIGURE 9. Histological pictures (TRAP staining) of PUR/HA and PUR/TCP composites at week 4. I, implants; NB, new bone formation, The black

arrows: TRAP positive multinucleated cells. Scale bars: 100 lm.





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formation at the surface of both HA/PUR and TCP/PUR

composites, which is consistent with lCT images. Higher

magnification images revealed cellular infiltration into the

materials. No inflammatory response was observed at week

4. As observed in Figure 8(A), HA/PUR composites showed

evidence of remodeling near the base of the implant.

However, the size of the original implants for both treat-

ment groups changed only minimally, suggesting that theextent of remodeling in the composites was low. Histological

sections stained for TRAP (Figure 9) showed osteoclast-

mediated resorption at the boundary between the implants

and newly formed bone.

DISCUSSION

Multiple CaP/polymer composites with varying porosities

and filler contents have been studied as biomaterials.10

These systems typically incorporate filler contents far below

the random close packing limit (RCP) of spheres ($64

vol%),29 and b-TCP/polymer composites have been reported

to decrease in strength as the amount of b-TCP increases.10

However, another study has shown that varying the fillercontent of HA/chitosan (CS) composites has a minimal

effect on the strength of the composites at loadings under

80 wt % ($64 vol %).11,29 In this study, varying the filler

content from 70 to 79 wt % (56.866.2 vol %) for the CaP/

PUR composites had no significant effect on strength. Con-

sistent with previous reports that HA is stronger than TCP,3

HA/PUR composites exhibited greater compressive modulus

and strength values compared to the b-TCP/PUR compo-

sites. At the 70 wt % filler content, there were no signifi-

cant differences in the compressive modulus in the treat-

ment groups. However, when the filler content was

increased to 79 wt %, there was a significant difference,

suggesting a greater contribution of the filler composition at

the higher loading. Therefore, we focused on 79 wt % CaP/

PUR composites in the subsequent in vitro and in vivo

experiments. The strength of the HA/PUR composites (87.0

MPa) was lower than values reported for chitosan (CS)/HA

composites, which were also prepared at 80 wt % HA (166

MPa).11 However, the compressive modulus of HA/PUR

composite materials (4.3 GPa) was an order of magnitude

higher than that of the CS/HA composites (416 MPa). Con-

sidering that compressive modulus and yield strength of the

PUR alone were 0.99 GPa and 40 MPa, respectively, the CaP

particles appear to be providing substantial mechanical

reinforcement of the composites.

The in vitro degradation rate of CaP/polymer composites

can vary substantially depending on the polymers and the

ceramic components, as well as the manufacturing meth-

ods.3032 The CaP/PUR composites in this study degraded

slowly in vitro, with the degradation rates in PBS ranging

from 0.8 to 2.0 wt %/week. The in vitro degradation rates

of HA/PUR and TCP/PUR composites were similar to those

measured in other CaP degradation studies,33,34 as evi-

denced by the fact that both materials retained 8595% of

their original mass after 7 weeks. Another study has

reported that CaP/polymer composites degraded more

slowly and maintained their shape longer than the pure

polymer.35 However, in the present study, both HA/PUR and

TCP/PUR composites degraded faster than the PUR control.

While TCP is more water-soluble than HA,36,37 HA/PUR

degraded faster than both TCP/PUR and the PUR control in

this study, suggesting that at early time points the primary

mechanism of degradation of the HA/PUR composites is dis-

solution of the HA phase. Additionally, high HA content may

influence the pH of the surrounding microenvironment,38

which can influence the polymer degradation rate.39

Cellular proliferation was higher on the surface of the b-

TCP composites. Previous studies have suggested thatb-TCP

can enhance osteoblast viability and proliferation, because

calcium and phosphate ions stimulate osteoblastic activ-

ity.3,21,40 In contrast, the dissolution of crystalline HA is

slow and reduces the pH of the surrounding microenviron-

ment, thereby slowing cell growth.38 Similarly, in this study,

the b-TCP/PUR composites supported a significantly higher

proliferation rate of osteoprogenitor cells compared with

the HA/PUR composites, which is thought to result from the

dissolution of b-TCP particles exposed on the surface of

the composites. Interestingly, the filler type did not have asignificant effect on ALP activity of the cells.

The remodeling of CaP/polymer composites in vivo has

been observed in several studies. HA/PLLA composites

implanted in rabbit femoral plug defects have taken up to

seven years to resorb and remodel.12 In this study, both ra-

diographs and histological sections show appositional bone

growth at the surface of the CaP/PUR composites, which

has also been observed for allograft/PUR composites

implanted in the rabbit distal femur.19 However, CaP/PUR

composites showed substantially less resorption and cellular

infiltration compared with allograft/PUR composites. Osteo-

clasts infiltrated and resorbed the CaP/PUR composites

near the bone-implant interface, as confirmed by TRAP

staining (Figure 9). Although there is limited evidence of

remodeling at the early time point investigated (4 weeks),

infiltration of osteoclasts near the implant-bone interface

suggests that at later time points the CaP/PUR composites

may remodel via slow reverse creeping substitution,4143 as

reported previously for allograft/PUR composites. However,

the rates of cellular infiltration and resorption were sub-

stantially less than those observed for allograft/PUR compo-

sites at similar filler loadings.19 The SEM images (Figure 2)

indicate that the CaP particles were fractured by the com-

pression molding process, which reduced the size of many

of the particles to


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reported to undergo up to 70% resorption by osteoclasts af-

ter 14 days,46 resorb faster than HA particles (0.02 lm3

lm2 day1)47 in vitro. These observations suggest that the

slower resorption rate of CaP composites could also be

attributed to the differences in composition between CaP

and allograft.

In this study, we examined the in vivo bioactivity of

CaP/PUR composites using a rat femoral plug defect modelwith a short-term observation period. Large animal models

with a long-term observation may be required in the future

to further investigate the osteoconductive ability and full

remodeling of the materials. However, the data from this

study suggest the potential of CaP/PUR composites for

weight-bearing implants as a biocompatible, osteoconduc-

tive, and resorbable material.

CONCLUSION

CaP/PUR composites have been synthesized using a two-

component polyurethane derived from LTI. The mechanical

properties of the composites suggest that they could be

useful for weight-bearing applications because the PURincreased the compressive strength of the CaP. Cell culture

studies showed that CaP/PUR composites were biocompati-

ble, with b-TCP further enhancing the cell viability and

proliferation. CaP/PUR composites also supported the

osteogenic differentiation of the osteoblastic cells. When

implanted in the distal femurs of rats, CaP/PUR composites

were shown to be biocompatible and osteoconductive with

no adverse responses observed. Histological sections

revealed evidence of infiltration of osteoclasts and resorp-

tion of CaP near the bone-implant interface, as well as appo-

sitional remodeling via slow reverse creeping substitution.

The current study suggests that CaP/PUR composites could

be a potentially useful option for weight-bearing implants.

ACKNOWLEDGMENTS

The authors thank Javier M. Esparza for his kind help for cell

culture and in vivo animal study.

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