polymer–calcium phosphate cement composites for bone substitutes

Polymer–calcium phosphate cement composites forbone substitutes

Rafal A. Mickiewicz,1 Anne M. Mayes,1 David Knaack2

1Department of Materials Science and Engineering, Massachusetts Institute of Technology,Cambridge, Massachusetts 02139-43072ETEX Corporation, 38 Sidney Street, Cambridge, Massachusetts 02139

Received 17 October 2001; revised 18 December 2001; accepted 11 January 2002

Abstract: The use of self-setting calcium phosphate ce-ments (CPCs) as bioresorbable bone-replacement implantmaterials presently is limited to non-load-bearing applica-tions because of their low compressive strength relative tonatural bone. The present study investigated the possibilityof strengthening a commercially available CPC, �-BSM™,by incorporating various water-soluble polymers into thecement paste during setting. Several polyelectrolytes, poly-(ethylene oxide), and the protein bovine serum albumin(BSA) were added in solution to the cement paste to createcalcium phosphate–polymer composites. Composites for-mulated with the polycations poly(ethylenimine) and poly-(allylamine hydrochloride) exhibited compressive strengthsup to six times greater than that of pure �-BSM™ material,with a maximum value reached at intermediate polymercontent and for the highest molecular weight studied. Com-posites containing BSA developed compressive strengths

twice that of the original cement at protein concentrations of13–25% by weight. In each case, XRD studies correlate theimprovement in compressive strength with reduced crystal-lite dimensions, as evidenced by a broadening of the (0,0,2)reflection. This suggests that polycation or BSA adsorptioninhibits crystal growth and possibly leads to a larger crystalaspect ratio. SEM results indicate a denser, more interdigi-tated microstructure. The increased strength was attributedto the polymer’s capacity to bridge between multiple crys-tallites (thus forming a more cohesive composite) and toabsorb energy through plastic flow. © 2002 Wiley Periodi-cals, Inc. J Biomed Mater Res 61: 581–592, 2002

Key words: hydroxyapatite; injectable bone substitute; poly-electrolyte adsorption; calcium phosphate cement; compos-ite

INTRODUCTION

Medical procedures to address bone-related injuryare prevalent in the United States,1 with around900,000 hospitalizations for fractures2 and over800,000 grafting procedures annually.3 Calcium phos-phates (CPs) are particularly promising as bone-substitute materials because of their similarity topoorly crystalline hydroxyapatite (PCHA), the min-eral component of bone. In addition to being nontoxic,they are biocompatible, not recognized as foreign inthe body, and, most important, they exhibit bioactivebehavior.

CPs are integrated into bone tissue by the same on-

going processes active in the remodeling of healthybone, that is, through the resorption and deposition ofbone mineral. This leads to an intimate physicochem-ical bond between CP implants and bone, termed os-seointegration.4–13 CPs also are known to support os-teoblast adhesion and proliferation.9,14,15 Because thisunique bioactivity is highly desirable, CP compoundsare widely studied and used as bone replacements oras coatings on implants.9–13,16–18

The development of self-setting calcium phosphatecements (CPCs) has extended the application of CPs toinjectable bone substitutes that can be shaped andmolded to fit irregular defects, with osseointegrativeproperties comparable to or better than bulk CPs.19

CPCs exhibit mechanical properties superior to othernonsetting injectable bone substitutes, and comparedwith acrylic cements, CPCs do not involve potentiallytoxic reagents or strongly exothermic setting reactions.

CPCs usually are a mixture of two or more CPs thatdissolve in aqueous solution, yielding a supersatu-rated solution of the desired final CP product. Thedesired phase then precipitates out, growing in the

Correspondence to: A. Mayes; e-mail: [email protected] grant sponsor: ETEX Corporation (Cambridge,

MA)Contract grant sponsor: National Institutes of Health; con-

tract grant number: 1R0GM59870-01

© 2002 Wiley Periodicals, Inc.

form of needle-like crystals that eventually interlock,giving rigidity to the cement. The most common CPCsyield a poorly crystalline, precipitated HA similar instructure to natural bone mineral.19–25 A number ofCPCs currently are available commercially.18,26,27

However, due to their limited compressive strength,they are restricted primarily to non-stress-bearing ap-plications. These include uses in maxillofacial surgery,the repair of cranial defects, and dental fillings.18,26,27

In order to improve the mechanical properties ofCPCs, a number of researchers have blended poly-mers with CP cements and met with promising re-sults. Durucan and Brown28,29 made �-tricalciumphosphate/poly(lactic acid) (�-TCP/PLA) and�-TCP/poly(lactic-co-glycolic acid) (PLGA) blendswith a subsequent hydrolysis of �-TCP to calcium-deficient hydroxyapatite (CDHA), which showed amodest improvement over the pure cement.

Fujishiro et al.30 added gelatin to their cement for-mulations, primarily to stabilize the paste in aqueoussolution before it develops adequate rigidity, andfound that they were able to get more than a 50%improvement of the compressive strength. They alsodemonstrated an improvement in mechanical proper-ties by adding rod-like hydroxyapatite and CaTiO3powders to the cements. Miyazaki et al.31,32 used anumber of polymers, including poly(acrylic acid)(PAA) and poly(vinyl alcohol) (PVA) to improve theproperties of a tetracalcium phosphate–dicalciumphosphate dihydrate (TTCP-DCPD) cement. Theynoted marked increases (up to threefold) in mechani-cal properties, but with an unacceptable reduction ofworkability and setting time. Dos Santos et al.33 re-ported similar results using sodium alginate and so-dium polyacrylate.

Herein, the influence of an added polymer compo-nent on the structure and properties of the bone sub-stitute material �-BSM™ is studied. As a CPC,�-BSM™ has shown very good performance, both invitro and in vivo,34,35 stimulating bone formation, re-sorbing in a timely fashion, and exhibiting no adverseside effects. Furthermore, �-BSM™ displays endother-mic setting behavior (hardening at 37°C), and allowsfor ample working time at room temperature. How-ever, the final cement suffers from a relatively lowcompressive strength (∼10 MPa), which limits its ap-plicability in orthopedics.

In light of the preceding discussion, we endeavoredto improve the mechanical properties of the cement byadding a water-soluble polymer during setting. Draw-ing on results from the biomineralization literature,polyelectrolytes were chosen as candidate polymercomponents because of their known tendency to ad-sorb to CP compounds and to influence their crystal-lization behavior.36–44

Previous work has shown that proteins togetherwith charged molecules and polymers can inhibit CP

crystal growth by binding ions in solution and/or ad-sorbing onto crystal growth sites.36–38,42 Preferentialadsorption of such molecules to specific crystal faceshas been attributed to the complementarity betweenthe charged groups on the adsorbing species and thoseon the crystal surface.36,37,39–42 One might thereforeexpect the incorporation of charged polymers to influ-ence the crystallization and, consequently, the me-chanical properties of �-BSM™ by similar mecha-nisms.

MATERIALS AND METHODS

Sample preparation

�-BSM™, an apatitic calcium phosphate bone substitute,was provided by ETEX Corporation (Cambridge, MA). Thematerial is an injectable bone substitute that sets at bodytemperature (37°C), forming a poorly crystalline hydroxy-apatite phase, and is composed primarily of two calciumphosphates. The first is an amorphous calcium phosphate(ACP) with a Ca/P ratio of 1.54 ± 0.05 and a submicronparticle size; the second is a dicalcium phosphate dihydrate(DCPD or brushite) with a particle size of 10–20 �m.18,27,35

The chemical structures of the polymers used are shownin Figure 1. Poly(diallyldimethylammonium chloride)(PDMAC, Mw ∼400,000–500,000 g/mol), poly(allylamine hy-drochloride) (PAH15, Mw ∼15,000, and PAH70, Mw ∼70,000g/mol), poly(ethylenimine) (PEI750, Mw ∼750,000 g/mol),and poly(sodium 4-styrenesulfonate) (SPS, Mw ∼70,000g/mol) were purchased from Aldrich Chemical Company,Inc. (Milwaukee, WI). PEI (PEI10, Mw ∼10,000 and PEI70,Mw ∼70,000 g/mol) and poly(ethylene oxide) (PEO, Mw

∼100,000 g/mol) were purchased from Polysciences, Inc.(Warrington, PA). Bovine serum albumin (BSA) was pur-chased from Sigma Chemical Company (St. Louis, MO).

Standard cylindrical (diameter = 6 mm, height = 12 mm)

Figure 1. Chemical structures of polymers used.

582 MICKIEWICZ, MAYES, AND KNAACK

compressive strength test specimens of �-BSM™ and�-BSM™/polymer composites were prepared in stainless-steel molds. For the five-sample molds, 3 g of �-BSM™ pow-der were mixed with 1.7–3.5 mL of deionized water (nomi-nal resistivity, ∼18 M�cm) or polymer solution to achieve asolid-to-liquid ratio (i.e., powder-to-solution ratio in g:mL)of approximately 1.25:1, as suggested by the manufacturer.The actual solution volume used was determined by theamount necessary to produce a workable paste and de-pended on polymer identity and concentration (see Table I).This paste was blended using mortar and pestle, then firmlypacked by hand into the mold. The samples were thenwrapped in a moist KimWipe™ and placed in an air incu-bator held at 37° ± 1°C for about 1 h (setting times varieddepending on polymer identity and concentration). Uponsetting, the sample ends were filed flush with the mold to

insure that the test specimens had flat and parallel ends, andthen the samples were carefully removed. The samples wereair dried at room temperature overnight prior to mechanicaltesting.

Sample characterization

Compressive strength properties of the cylindrical speci-mens were tested using an Instron (Canton, MA) Model No.1125 at a crosshead speed of 0.05 in/min (∼0.02 mm/min).Compressive strength values were determined by dividingthe maximum load by the original cross-sectional area. Re-sults for 3–5 specimens were converted to megapascals

TABLE IMechanical Test Sample Preparation Details

SamplePowder-to-liquid

ratio [g/mL]Paste

consistencySettingtime [h]

Numberof samples

Final polymercontent [wt%]

�-BSM™* 1.25 firm 0.75 10 0BSA (5) 1.25 wet, syrupy 0.75 5 5BSA (10) 1.25 wet, syrupy 0.75 5 10BSA (15) 1.5 slightly dry 0.75 5 13BSA (20) 1.36 wet, syrupy 0.75 3 19BSA (25) 1.38 syrupy, sticky 0.75 5 24PAH15 (5) 1.76 slightly wet 1.5 4 4PAH15 (10) 1.67 slightly wet 1 5 8PAH15 (15) 1.62 slightly dry 1 5 12PAH15 (20) 1.43 slightly dry 1.5 5 18PAH15 (25) 1.38 firm 1 5 24PAH70 (5) 1.5 syrupy 1.25 5 4PAH70 (10) 1.5 syrupy 1.25 4 9PAH70 (15) 1.58 dry, firm 1 4 12PAH70 (20) 1.43 dry, firm 1 4 18PAH70 (25) 1.3 sticky 0.75 5 24PDMAC (5) 1.2 thick 0.75 5 5PDMAC (10) 1.15 thick 0.75 5 11PDMAC (15) 0.97 sticky 0.75 5 17PEI10 (5) 1.6 wet 2.5 4 4PEI10 (10) 1.67 wet, syrupy 2.25 4 8PEI10 (15) 1.43 syrupy 1.5 4 13PEI10 (20) 1.3 syrupy 2.5 4 19PEI70 (5) 1.5 thick, syrupy 0.75 5 4PEI70 (10) 1.43 thick, syrupy 1.5 4 9PEI70 (15) 1.37 syrupy, sticky 3.5 4 14PEI70 (20) 1.11 syrupy, sticky 1.5 4 21PEI750 (5) 1.5 wet, fast drying 1.5 5 4PEI750 (10) 1.5 dry, firm 1.5 7 9PEI750 (15) 1.43 dry, sticky 2.5 4 13PEI750 (20) 1.07 sticky, firm 13 3 22PEI750 (25) 0.86 sticky, firm 13 3 33PEO (5) 1.15 sticky, firm 0.75 5 5PEO (10) 1.07 sticky 0.75 5 12PEO (15) 0.97 sticky 0.75 5 19SPS (5) 1.25 syrupy 0.75 5 5SPS (10) 1.25 syrupy 0.75 5 10SPS (15) 1.25 syrupy 0.75 5 15SPS (20) 1.25 syrupy, sticky 0.75 5 20SPS (25) 1.25 syrupy, sticky 0.75 5 25

Values in parentheses refer to the theoretic polymer content in wt %. *Several different batches of �-BSM™ powder wereobtained from ETEX Corporation. Each new batch was mechanically tested to insure that there were no significant discrep-ancies in compressive strength in the different lots used. The values presented are representative of all the batches tested.

583POLYMER–CP CEMENT COMPOSITES

(MPa), and recorded as the average ± standard deviation.Energy-to-failure was determined by computing the areaunder the force deflection curves and is reported in Joules.

Scanning electron microscopy (SEM) was performed us-ing a JEOL 6320 field-emission scanning electron microscope(FESEM). Sample fracture fragments were mounted on con-ducting carbon tape, vapor coated with gold-palladium, andvisualized using an accelerating voltage of 5 keV.

Statistical analysis of the crystal structure and grain sizewas accomplished through X-ray diffraction studies. Samplefracture fragments were analyzed with a Rigaku RU300 (18kW) powder X-ray diffractometer operating at 60 kV and300 mA, using Cu K� radiation with 0.5° scatter and diffrac-tion slits and a 0.3-mm receiving slit. Samples were scannedat 4°/min with a 0.02° sampling interval over the range 2° �2� � 60°.

For crystal size determination, the hydroxyapatite (0,0,2)reflection at 2� ∼ 26° was used. Samples were scanned at0.25°/min with a 0.01° sampling interval over the range 24°� 2� � 28°. Three scans were performed on each of thesamples, and the baseline-subtracted data were fit using Ka-leidaGraph (Marquardt-Levenberg algorithm) to a Gaussiancurve to obtain an estimate of the breadth of the peak usingthe fitted value of the full width at half the maximum inten-sity. This value was used to determine the size of the crystalsemploying the Scherrer formula:45

t =�

B cos �B, (1)

which relates the thickness of the crystal, t, to the wave-length of the incident radiation, �, the breadth of the peak, B

(in radians), and the Bragg angle, �B. The R-value, used asthe figure of merit for the Gaussian fits obtained, rangedfrom 0.878 to 0.996.

RESULTS

Mechanical testing

The compressive strength (CS) results for all com-posite materials are shown in Figure 2. The SPS, PD-MAC, and PEO composites [Fig. 2(a)] show little or noincrease in the compressive strength over the originalcement. In fact, both the SPS and PDMAC compositesshow a slight decrease in compressive strength. Bycontrast, the composites containing the polycations,PAH and PEI, exhibit remarkable strength increases[Fig. 2(c,d)]. PAH incorporation increases the com-pressive strength fourfold to around 45 MPa, similarto the two lower MW PEI composites.

The greatest improvement was seen with the com-posite formulated with PEI of high MW (750,000g/mol), peaking at a CS of 62 MPa. These polycationformulations also exhibit an optimal value of the poly-mer content in the composite, with the maximumcompressive strength achieved at a polymer contentbetween 5 and 10% by weight. In addition, there is aclear dependence of CS on the MW of the polymer,

Figure 2. Compressive strength: (a) PEO/, PDMAC/, and SPS/�-BSM™ composites; (b) BSA/�-BSM™ composites; (c)PAH/�-BSM™ composites; and (d) PEI/�-BSM™ composites.


with the PEI750 composites showing much higherstrength than the lower MW PEI composites. Interest-ingly, in both the PAH and PEI systems, the PAH15and PEI10 polymers exhibit a higher strength at poly-mer contents of 5% by weight as compared to thePAH70 and PEI70 polymers, respectively, at the sameconcentration.

Finally, an improvement in CS also was noted forthe BSA composites, though not nearly as pronouncedas that of the two polycations above. The CS increasedto just over 20 MPa at BSA contents above 13% byweight [Fig. 2(b)]. In general, the energy-to-failure(EF) data follow the same trends as the CS data (Fig.3). It is noteworthy that although the CS of thePDMAC composites did not change much, there was atwofold increase in the EF due to a notable rise instrain to failure.

X-ray diffraction characterization

An X-ray diffraction pattern typical of the compos-ites is shown in Figure 4. Two phases can be identifiedfrom this reflection pattern. The first is brushite, iden-tified by the sharp, narrow reflections. Brushite(DCPD) is one of the initial components of the

�-BSM™ powder. Apparently it did not dissolve com-pletely during the setting of the cement.

It is worth mentioning that the brushite reflectionsappear even in the pure cement (i.e., �-BSM™ pluswater with no polymer added), but they did not ap-pear in three of the PEI composite formulations stud-ied, namely 10% PEI10, 15% PEI70, and 20% PEI750.

Figure 3. Energy-to-failure: (a) PEO/, PDMAC/, SPS/�-BSM™ composites; (b) BSA/�-BSM™ composites; (c) PAH/�-BSM™ composites; and (d) PEI/�-BSM™ composites.

Figure 4. Typical XRD pattern of the �-BSM™ composites.The dominant phase reference spectra are shown for com-parison and the (0,0,2) reflection of hydroxyapatite is la-beled.


The second phase that can be deduced from the pat-tern is that of HA, which either was poorly crystallineor, more likely, nanocrystalline, as evidenced by thebroad peaks located in the regions of the HA reflec-tions.

The (0,0,2) reflection of HA is labeled in Figure 4and is seen to be quite broad compared to the brushitereflections. This reflection was chosen to study thecrystal size as it is quite prominent in the patterns ofall the composite materials and is sufficiently removedfrom other reflections to allow for an unambiguousdetermination of peak width.

The results from the analysis of the peak width ofthe (0,0,2) HA reflection are plotted in Figure 5 ascrystal size (t) versus polymer content. Since the dataare not corrected for instrument resolution and ther-mal vibration, the values obtained should be consid-ered only as a rough measure of the crystal size. Nev-ertheless, this size scale is corroborated in the high-magnification SEM micrographs of the fracturesurfaces, discussed below, which exhibit crystalliteswith at least one dimension on the order of ∼20 nm. Itis interesting to note that for systems that did not ex-hibit improved compressive strength, the measuredcrystal size increases relative to pure �-BSM™. Bycontrast, a decreasing trend in crystal size is observedin systems that exhibit improved mechanical proper-ties.

DISCUSSION AND CONCLUSIONS

From SEM analysis, it was found that all the com-posite systems that showed little or no improvementin mechanical properties over pure �-BSM™ cementexhibited similar morphologies, morphologies thatwere virtually identical to that of the pure cement [Fig.6(a–d)]. The micrographs depict ∼0.5-�m “spiky”spheric agglomerates, presumably made up of apatiticnanoscale crystals. It is easy to envisage that the inter-locking of these needle-like protrusions leads to thesetting and rigidity of the cement.

At high magnification, the agglomerates appear tobe coated by the organic component, which followsthe contours of the crystallites but does not change theoverall microstructure significantly [Fig. 6(e,f)]. Fibril-lar bridges between the crystal clusters are observed inthe PDMAC composites, providing direct evidence ofthe polymer [Fig. 6(f)]. While the overall microstruc-ture appears roughly unchanged by the addition ofpolymer in these composites, the XRD data in Figure5(a) indicate an increase in the crystal size, suggestingthat all these polymers may promote growth.

It is curious that the polymers do not provide forsome level of cohesion between the crystal aggregatesin these systems, which would improve the CS. Forthese cements, however, the limiting factor may notnecessarily be the cohesion of the polymer but rather

Figure 5. Crystal size calculated from XRD (0,0,2) reflection: (a) PEO/, PDMAC/, and SPS/�-BSM™ composites; (b)BSA/�-BSM™ composites; (c) PAH/�-BSM™ composites; and (d) PEI/�-BSM™ composites.


the adhesion between the polymer and the inorganicmatrix. For example, PEO, having no charged groups,might be expected to exhibit weaker binding to apatitecrystals than the polyelectrolytes studied. SPS, on theother hand, contains negatively charged groups thatarguably could interact more strongly with surfaceCa2+ ions. Nevertheless, its addition does not improvethe CS, and XRD analysis points to an increase in crys-tal size. As seen in previous studies, the presence of aparticular functional group does not necessarily implyinhibitory properties. For example, although some

poly(carboxylic acids) are known to inhibit CP crystalgrowth by binding to surface Ca2+ sites, others haveno effect on crystal growth.39,41

By analogy, the molecular structure of SPS maysterically hinder strong binding to apatite surfaces.Similarly, the polycation PDMAC, which does notprovide the CS enhancement found with the polyca-tions PAH and PEI, has two bulky methyl groups (seeFig. 1) that may interfere with electrostatic interactionsbetween the positively charged nitrogen and the sur-face anions of the apatite crystals. It can be argued,

Figure 6. SEM micrographs of cement morphologies: (a) �-BSM™; (b) PDMAC (10%); (c) PEO (10%); (d) SPS (10%); (e) SPS(5%); and (f) PDMAC (15%). Original magnification: (a–d) ×10,000; (e,f) ×50,000.


then, that PDMAC, PEO, and SPS behave in a similarfashion, perhaps promoting crystal growth by reduc-ing the surface energy of the growing crystals46,47

through their presence in solution, or by adsorbingweakly to crystal surfaces.

Composites incorporating BSA exhibit a complexbehavior similar to that seen in the literature for vari-ous proteins, including BSA.47 XRD results show anincrease in the crystal size for BSA contents less than10% by weight, followed by a decrease in crystal sizeat higher percentages. The ability of BSA to enhanceCP crystal growth at low concentrations and to inhibitgrowth at higher concentrations was demonstrated byCombes et al.,47 albeit at lower concentrations than theones studied here. Apparently at low concentrations(<10 gL−1), enough BSA is available to just stabilize thenuclei and promote growth of octacalcium phosphatecrystals while at higher concentrations, crystal growthis impeded by high BSA coverage.

Although the net charge on BSA at neutral pH is−17, the protein contains both positively and nega-tively charged residues.48 The arrangement of thesecharges on the molecule may influence crystal growthbehavior and also lead to a more cohesive cement forthe higher BSA contents since complementarity be-tween the charged groups on the protein and apatitesurface is important in influencing crystal growth.40–42

From SEM analysis, it is apparent that, like thePDMAC, PEO, and SPS composites, the microstruc-ture of composites with 10 wt % BSA [Fig. 7(a)] re-sembles that of pure �-BSM™ [Fig. 6(a)]. At higherBSA contents, however, the composite appears morecohesive and dense [Fig. 7(b)], which may very wellexplain the improved CS. The spheric clusters fuse toform a much more compact and interconnected mate-rial, with the organic component acting as an adhe-sive.

The most dramatic improvements in mechanicalproperties were observed with the PAH and PEI com-posite cements. Both systems exhibited similar behav-

ior, with a maximum CS developed at intermediatepolymer concentrations. From the micrographs in Fig-ure 8(a,b), it is evident that these composites are verydense, which correlates well with their enhancedstrength compared with the systems shown in Figure6(a–d). It is likely that this densification results fromadsorption of the polycations to surfaces of the grow-ing apatite crystals. This is reflected in the XRD data,which indicate a decrease in the crystal size throughthe broadening of the HA (0,0,2) reflection.

Other researchers also have noted an improvementin CS resulting from a decreased crystal size. Fernan-dez et al.49 suspected that smaller crystal size and in-terconnected structure, resulting from carbonate in-corporation in their CPC formulations, led to bettermechanical properties, but they were not able to de-termine this from their micrographs. Lawson andCzernuska50 demonstrated improved mechanicalproperties of collagen–apatite composites by decreas-ing the inorganic crystal size, citing a denser packingof the crystals.

Tan and McHugh51 made calcium aluminate ce-ment/poly(vinyl alcohol) composites with improvedmechanical properties by incorporating smaller cal-cium aluminate particles. Finally, in an XRD studysimilar to the one presented here, Otsuka et al.52 cor-related the enhanced mechanical properties of theirTTCP-DCPD CP cements with the smaller crystal sizesof the transformed HA phase.

At higher magnifications, composites with PAHand PEI are seen to be comprised of nanocrystallineagglomerates, smaller and more interpenetrated thanin the composites studied above, with an almost “wo-ven” appearance that hints at preferred crystal growthdirections during setting [Fig. 8(c,d)]. Since the inter-locking of crystallites is what largely determines CPCstrength,28,53 these images offer a clear explanation forthe enhanced mechanical properties these composites

Figure 7. SEM micrographs of BSA/�-BSM™ cement morphologies: (a) 10%; (b) 20%. Original magnification: ×10,000.


exhibit over those shown at the same magnification inFigures 6(e,f), for example.

Beyond inducing the formation of a more compactmicrostructure, the polycations PEI and PAH mayprovide further strengthening mechanisms to thecomposite by bridging between multiple crystals orcrystal clusters. This would result from strong bondsbetween the polycations and the CP crystal faces, forexample between the positive amines of the polyca-tions and the negative phosphate or hydroxyl groupsof the HA surface. The knitted or woven appearanceof the microstructures in Figure 8 could indeed be aresult of the preferential adsorption of the polycationsto particular faces of the crystal, leading to increasedanisotropy as other faces grow relatively unchecked.

Such preferential adsorption of proteins, polyelec-trolytes, and other charged molecules to growing in-organic crystal faces has been reported previ-ously.40,41,54–56 For example, Bertoni et al.43,44 foundthat PAA adsorption onto growing HA crystals inhib-ited crystal growth more strongly in the direction or-thogonal to the c-axis of the crystal, which was ratio-nalized by a preferential interaction of PAA with thecrystal faces parallel to the c-axis. This led to a more

anisotropic, elongated crystal structure and, at highPAA concentrations, to clusters of HA nanocrystals.

The effect of polymer molecular weight on the me-chanical properties of the composites is also ratherinteresting. Composites prepared with 9 wt % PEI750showed the best mechanical performance. In additionto its highly branched structure, the high MW of thispolymer allows it to bridge numerous crystallites andengage in intermolecular entanglements, providingstrengthening mechanisms similar to those obtainedin semicrystalline polymers.51,57,58

It should be noted, however, that the PDMAC usedalso was of a high MW, but it did not exhibit the samedramatic improvement in CS. Nevertheless, the im-proved EF of the PDMAC composites [Fig. 3(a)]clearly suggests that this high MW polymer toughensthe composite by providing for energy dissipationthrough plastic flow.

For the PAH and PEI cements, the decrease in CS athigher concentrations coincides with changes in theappearance of the composite fracture surfaces, whichlook considerably smoother and more rounded (Fig.9). At these elevated concentrations the polymer ap-parently forms a thick coating on the crystal clusters,

Figure 8. SEM micrographs of polycation/�-BSM™ cement morphologies: (a) PAH70 (10%); (b) PEI750 (10%); (c) PEI70(5%); and (d) PAH15 (20%). Original magnification: (a,b) ×10,000; (c) ×50,000; (d) ×100,000.


preventing them from interlocking. The high polymercontent composites exhibit typical polymeric proper-ties of low stiffness (modulus) and plastic flow, indi-cated by their higher strain to failure. This plastic flow,at lower concentrations, contributes to the improve-ment of the CS by acting as an energy absorbingmechanism.59 However, when the polymer begins tointerfere with the interlocking of the crystals, the ce-ment loses its strength.28

Finally, the composites incorporating the lower MWPAH and PEI polymers each exhibit a maximum CSon the order of 40 MPa, but curiously, in both cases,this maximum is seen at lower concentrations than forthe composites incorporating the higher MW PAHand PEI polymers. This behavior can be attributed tothe powder-to-liquid (P/L) ratio (Table I). It is wellknown that the P/L ratio affects the final mechanicalproperties of a CPC, with an increased P/L ratio lead-ing to superior mechanical properties and a concomi-tant reduction in working time and paste workabil-ity.24,32,49,60

This increase in mechanical strength due to an in-crease in P/L ratio is correlated with a lower overallporosity of the CPC.49,60 Though our data generallyare consistent with this trend, particularly for thePAH15 and PEI10 composites, the P/L ratio was notkept constant in our experiments for the simple reasonthat the workability of the pastes was a prime concern.The powders were mixed with the polymer solutionsin such a way as to afford a cohesive workable paste,bearing in mind the end use of the material in clinicalapplications. Moreover, assigning the increase in CSsolely to P/L ratio does not explain, for example, theCS increase in going from 5% PAH70 to 10% PAH70since these formulations both had a P/L ratio of 1.5:1.

Similar discrepancies are found for the PEI750 com-posites when comparing the 5% and 10% polymer for-mulations, as well as when comparing the PAH15 toPAH70 formulations at both 15% and 20% polymer

content. In each of these cases, the P/L ratio is similar,but the compressive strength is significantly different.In fact, in the study by Miyazaki et al.,31 there was alsono apparent correlation between P/L ratio and com-pressive strength.

Collectively these results suggest that while P/L ra-tio may play a role, the polymer’s chemical structureand long-chain effects are equally important consider-ations. Furthermore, the XRD and SEM data seem toindicate a similar mechanism at work in all the com-posites, namely improved mechanical properties dueto smaller crystallites (or crystallites that grow prefer-entially), which results in a denser, more interdigi-tated composite. In summary, we suggest that the me-chanical properties of the �-BSM™ cement were im-proved by the combination of the influence of strongpolymer adsorption on crystal growth behavior andthe incorporated polymer’s ability to absorb energyand bridge across multiple crystallites.

The authors acknowledge the technical support of MikeFrongillo and Joe Adario and the helpful comments of Dr.Ali Tofighi.

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polymer–calcium phosphate cement composites for bone substitutes

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