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A parametric study on the processing parameters and properties of a porous poly(DL-lactide-co-glycolide) acid 85/15 bioscaffolds.

INTRODUCTION

Recently, there has been an increased need for the design and the development of novel-engineered tissues because the demand for organ transplants far outpaces the supply (1-10). The fundamental concept of tissue engineering is that cells can be isolated from a patient and seeded onto a carrier. One currently used approach for the seeding of cells is carried out using a hybrid system that consists of a mixture of man-made materials (scaffold) and cell or tissue. The scaffold, which is often comprised of a porous biodegradable polymer, provides a temporary support for cell growth. As the cells grow and divide within the porous scaffold, they create their own support matrix, and the polymer, which is no longer needed, degrades over time. The resulting tissue is then grafted back into the same patient to function as a replacement (5), (9-12). This approach has been used with some success in an attempt to grow human tissues, such as skin (13), ligaments (11), (14), cartilage (15-17), liver (11), nerves (18), heart valves (19), soft tissues (20), (21), bone (3), (9), (11), (16), (22-28), and bone marrow (29), to name a few. To date, however, it has only successfully yielded skin tissue and cartilage for patient treatment (4). Nevertheless, once this technique has been mastered, it could provide treatment for a wide range of dysfunctional tissues that are not capable of regenerating on their own.

Tissue engineering still faces many challenges, one of them being the perfection of the scaffold (10), (30-31). The primary consideration in the fabrication of a porous scaffold is the choice of the material used. The scaffold should be made of a material that is biocompatible, and that degrades into nontoxic products. It should also have a controllable degradation rate to match the pace of cell or tissue growth (9), (14), (16), (32-33). The second issue is the ability to control the morphology of the pores inside the scaffold. The porosity, pore size, and level of interconnectivity are critical factors that allow cell seeding and cell growth in the scaffold. Highly porous scaffolds are also desired for enabling the diffusion of nutrients to, and waste products from the implant, as well as for vascularization (9), (14), (16), (32), (33). Finally, the scaffold should have enough mechanical strength to provide a suitable stress environment for the tissue (9), (14), (16), (32).

Several studies have been executed using different techniques for processing porous scaffolds comprised of biodegradable polymers; each have their respective advantages and disadvantages (1), (5-7), (14), (16-17), (22), (28), (34-42). Most techniques use either high temperatures or organic solvents, which prevent the incorporation of vascular growth factors into the scaffold during its formation. Organic solvents also tend to be harmful to the growing cells if they are not removed fully from the scaffold (43), (44). In contrast, the gas foaming/salt leaching method does not require the use of high temperatures or organic solvents and can permit the incorporation of vascular growth factors inside the scaffold during its fabrication.

Studies have been conducted using the gas foaming/salt leaching technique to produce scaffolds made of biodegradable polymers (1), (44), (45). However, there is limited information available regarding the effects of the processing parameters on the scaffold's physical properties. This study reports the effects of saturation time (ST), saturation pressure (SP), and NaCl/polymer mass ratio (NaCl/PMR) on the scaffold density, porosity, average pore size, pore density (PD), and Young's modulus in compression using the biodegradable polymer 85/15 poly(DL-lactide-co-glycolide) acid.

EXPERIMENTAL SECTION

Materials

In this study, 85/15 poly(DL-lactide-co-glycolide) acid (PLGA 85/15) was used. It was purchased from Lake-shore Biomaterial Inc (Birmingham, AL). PLGA 85/15 is an amorphous polymer that has a glass transition temperature between 50 and 55[degrees]C and a specific gravity of 1.27 g/ml. Sodium chloride (NaCl), obtained from Fisher Scientific, and distilled water (d[H.sub.2]O) were used in the gas foaming/salt leaching process. Finally, carbon dioxide ([CO.sub.2]) gas cylinders obtained from Praxair (Kemptville, Canada) were also used.

Experimental Procedures

The PLGA 85/15 pellets were ground using a 6850 Freezer/Mill from the SPEX CertiPrep Group. The polymer pellets were placed in a vial that was prechilled by immersion in liquid nitrogen for 15 min, and then ground for a total of 6 min (three 2-min grinding periods were interspersed with 2-min recooling phases). The resulting polymer powder and the NaCl particles were then sieved separately; the former yielded particles that varied between 106 to 500 [micro]m, whereas the latter produced particles in the 106 to 250 [micro]m range. Subsequently, several NaCl/polymer disks with different NaCl/PMRs were prepared. The total mass of these disks was held constant at 250 mg. The NaCl/PMRs used were 5, 10, 15, and 20. The NaCl/polymer mixture was first added to a round KBr die 12.8 mm in diameter and than compressed for 60 sec at 22,241.11 N in a Carver press. This produced solid disks that were ready to be foamed.

The gas foaming/salt leaching technique used in this experiment consisted of three steps (1), (44). The NaCl/ polymer sample was placed in a pressure vessel and saturated with [CO.sub.2] at various subcritical SPs and times. SPs of 4.14 and 5.52 MPa were applied for three different saturation periods--12, 24, and 72 hr. At the end of a given saturation period, a thermodynamic instability was created by rapidly releasing the [CO.sub.2] pressure in the vessel to the atmospheric pressure. NaCl/polymer samples were then placed in d[H.sub.2]O for 48 hr to dissolve the NaCl; a porous matrix was formed subsequently. The d[H.sub.2]O was replaced every 24 hr. The amount of NaCl removed from the samples was also verified by comparing the samples' masses before and after leaching. A minimum of three samples was prepared for each combination of parameters.

Sample Characterization

Density, Porosity, and Relative Density. The density of the scaffold ([rho]*) was obtained from Eq. 1, where the mass (m) and volume (V) were measured after the leaching of NaCl was performed. The total volume of the scaffold was obtained by measuring the diameter and the thickness of the disk. Three measurements of the diameter and the thickness were taken and averaged. The relative density ([[rho].sub.r]) and porosity (P) of the samples were determined from Eqs. 2 and 3, respectively, where [rho] is the density of the unfoamed polymer, which was provided by the supplier.

[rho]* = [m/V] (1)

[[rho].sub.r] = [[rho]*/[rho]] (2)

P = (1 - [[rho].sub.r]) x 100 (3)

Average Pore Size, and Pore Density. The average pore size and PD were obtained with the aid of micrographs, which were taken using a digital microscope. The pores were counted using Image J software. The average pore size ([PS.sub.avg]) was then calculated using the number of pores and the two-dimensional area of each micrograph from Eq. 4, where H and L represent the height and length of the micrograph in mm, respectively, and N represents the number of pores per picture. The PD was calculated using Eq. 5, where [V.sub.f] and [V.sub.i] represent the final and initial volumes of the sample, respectively.

[PS.sub.AVG] = [square root of ([H x L]/[[pi]N])] x 2 (4)

PD = [([N/[H x L]] x 100).sup.[3/2]] x [[V.sub.f]/[V.sub.i]] (5)

Scanning Electron Microscopy. The pore morphology, pore size, PD, and level of interconnectivity were also evaluated using scanning electron microscopy. The samples were coated using a cold coating process by applying a thin layer of gold with the aid of a sputter coater (scanning electron microscopy (SEM) Coating Unit PS3). The gas pressure was set at 2 kPa, and the current was applied at 9 to 10 mA; the entire coating time lasted 70 sec. The edges of the coated samples and the SEM mounts were then painted with a conductive carbon paste. A JEOL scanning electron microscope (Model JSM 6060) was than operated at 20 kV, and images were acquired from several locations on each sample.

Compressive Young's Modulus. The compressive modulus of the scaffolds was measured at the ambient temperature using an Instron machine (Model 1122). The scaffolds were compressed between two plates with a constant deformation rate of 1 mm/min using a 5000 N load cell. A small preload was applied to each sample before the compression test to ensure that the entire scaffold surface was in contact with the plates. The strain was calculated using the displacement of the crosshead, and the compression modulus was determined from the slope in the elastic portion of the stress-strain curve. For each combination of parameters, a minimum of three samples were tested, and the average was calculated.

RESULTS AND DISCUSSION

Effects of Saturation Time and NaCl/Polymer Mass Ratio on the Scaffold Morphology

Figure 1 depicts the effects of the ST on the density of scaffolds comprised of varying NaCl/PMRs: 5, 10, 15, and 20. All the scaffolds in this part of the experiment were fabricated using a SP of 5.52 MPa. The figure shows that the change of scaffold's density was not significant when the saturation period was increased. However, it was observed that the density decreased as the NaCl/PMR increased. For a NaCl/PMR of 5, the density ranged from 0.1028 to 0.0988 as the ST was extended from 12 to 72 hr. Over the same ST increase, the density varied from 0.0831 to 0.0662 for a mass ratio of 10, from 0.0648 to 0.0534 for a mass ratio of 15, and finally from 0.0610 to 0.0677 for a mass ratio of 20. Typically, it would be expected that as the saturation period is extended up to the equilibrium concentration, the amount of gas that diffuses into the polymer matrix would increase; this would, in turn, theoretically decrease the density of the scaffold (46-48). In this study, however, this phenomenon was not significant, because the amount of polymer in the matrix was small relative to the NaCl content. It can also be due to the range of saturation periods chosen, which may have been close to the time needed to reach the equilibrium concentration.

[FIGURE 1 OMITTED]

The main function of the gas in this case was to decrease the glass transition temperature ([T.sub.g]) of the polymer, so that the polymer could bind and yield a structural matrix once the salt was leached out (49), (50). The gas was also used to foam the polymer, but in this experiment it was not the main mechanism responsible for affecting the density. The decrease in density due to the increase in the NaCl/PMR can be explained by the fact that a higher NaCl/PMR induces a larger amount of voids into the polymer matrix after the leaching of the NaCl. Ultimately, in this study, the density was mainly impacted by the leaching of the salt and not by the gas absorption.

Figure 2 elucidates the effects of the saturation time on the porosity of scaffolds constituted using the same array of NaCl/PMRs: 5, 10, 15, and 20. All the scaffolds in this part of the experiment were fabricated using a SP of 5.52 MPa. It was found that there was only a slight increase in porosity as the saturation period was extended. For all four of the NaCl/PMRs, the porosity was more than 92% and increased as the NaCl/PMR was increased. Figures 3 and 4 demonstrate that the average pore size and PD are independent of the saturation time for the four NaCl/ PMRs when a SP of 5.52 MPa was used. It can also be seen that the average pore sizes inside the scaffolds were between 170 and 188 [micro]m and that the pore densities increased from 2.79 X [10.sup.6] to 6.729 X [10.sup.6] pores/[cm.sup.3] as the NaCl/PMRs increased from 5 to 20. It would have been expected that as the saturation time increased up to the equilibrium concentration, the amount of gas dissolved in the matrix would have been augmented, which in turn would have caused an increase in the number of nucleation sites (47). Technically, this increase in nucleation sites would have produced a decrease in the average pore size and an increase in the PD. Once again, however, this effect was not observed in this experiment, as the amount of polymer in the matrix was small relative to the NaCl content, and the saturation periods used may have been close to the time required to reach the equilibrium concentration. The PD and pore size were, therefore, mainly affected by the NaCl that was leached out during the fabrication of the scaffolds and not by the saturation time. Because the porosity is dependent on the density and is inversely proportional to it, the results shown in Fig. 4 can be explained according to the same logic as Fig. 2 explains the leaching of NaCl as the primary mechanism affecting the scaffold properties. The results obtained from our experiments confirm this because it was found that the average pore size in the scaffold was constant and equal to the average size of the NaCl particles used to fabricate the matrix before leaching; this is also consistent with the findings recorded in the literature (44), (51). The PD was determined to be directly proportional to the NaCl/PMR, which once again agrees with the hypothesis that the main mechanism producing change was the leaching of NaCl and not the gas concentration when the saturation time was extended from 12 to 72 hr.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

Figure 5 illustrates different levels of interconnectivity and uniformity, as well as a high PD in the different scaffolds. The four samples were made from different NaCl/ PMRs (5, 10, 15, and 20) at a SP of 5.52 MPa and over a saturation period of 12 hr. The level of interconnectivity and the number of pores in the scaffold increased as the NaCl/PMR was increased. Using a NaCl/PMR of 20 produced a structure with large voids due to the high amount of NaCl that was removed during the leaching process. Moreover, it was observed that as the NaCl/PMR was reduced, the amount of polymer in the matrix available to form the walls of the pores increased; this resulted in a larger amount of material, which provided greater structural strength to the scaffold (Figs. 6 and 7, Table 1) and a larger surface area for cell adhesion.
TABLE 1. Effects of saturation pressure and NaCl/polymer mass ratio on
the Young's modulus in compression of the scaffold (MPa).

            NaCl/polymer mass ratio = 5  NaCl/polymer mass ratio = 20

Saturation   Saturation    Saturation     Saturation    Saturation
 pressure   time = 72 hr  time = 24 hr   time = 72 hr  time = 24 hr
  (MPa)

4.14            0.7915       0.8379         0.0739        0.1026
5.52            0.4688       0.3840         0.1788        0.1785


[FIGURE 5 OMITTED]

Effects of Saturation Pressure on the Scaffold Morphology

Tables 2 and 3 depict the effects of SP and NaCl/PMR on the scaffold density and porosity. It can be observed that as the SP was increased, the scaffold density decreased, and the porosity increased. For those scaffolds comprised of a NaCl/PMR of 5, the density varied from 0.1490 to 0.0952 and the porosity ranged from 88.27 to 92.51% as the pressure was amplified from 4.14 to 5.52 MPa. For the higher NaCl/PMR of 20, the density varied from 0.0806 to 0.0597, and the porosity ranged from 93.65% to 95.3% as the pressure was increased similarly from 4.14 to 5.52 MPa. All parameter combinations yielded scaffolds with porosities more than 92% except in the case where the SP and the NaCl/PMR were 4.14 MPa and 5, respectively. The decrease in density and the increase in porosity due to the increase in SP can be explained by the fact that a higher SP increased the amount of gas dissolved into the polymer portion of the matrix (46). From these two tables, it can also be surmised that the effect of the SP was more significant for scaffolds with a NaCl/PMR of 5 than those with a ratio of 20 due to the lower amount of polymer in the matrix when the latter NaCl/PMR was used. In this experiment, the density and the porosity were affected by two mechanisms: the NaCl was the primary one, whereas the SP had a smaller effect.
TABLE 2. Effects of saturation pressure and NaCl/polymer mass ratio on
the scaffold density (g/[cm.sup.3]).

            NaCl/polymer mass ratio = 5  NaCl/polymer mass ratio = 20

Saturation   Saturation    Saturation     Saturation    Saturation
 pressure   time = 72 hr  time = 24 hr   time = 72 hr  time = 24 hr
  (MPa)

  4.14        0.1314        0.149          0.08063       0.06768
  5.52        0.09876       0.09515        0.06773       0.05972

TABLE 3, Effects of saturation pressure and NaCl/polymer mass ratio on
the scaffold porosity (%).

            NaCl/polymer mass ratio = 5  NaCl/polymer mass ratio = 20

Saturation   Saturation    Saturation     Saturation    Saturation
 pressure   time = 72 hr  time = 24 hr   time = 72 hr  time = 24 hr
  (MPa)

  4.14         89.66         88.27          93.65         94.67
  5.52         92.22         92.51          94.67         95.30


Tables 4 and 5 indicate that the average pore size decreased slightly as the pressure was increased and was not affected by the change in the NaCl/PMR. The PD, however, was affected by both factors; it increased as the SP went from 4.14 to 5.52 MPa and as the NaCl/PMR went from 5 to 20. These tables also show that the average pore sizes were between 178 and 203 [micro]m, and the pore densities varied from 1.51 X [10.sup.6] to 5.71 X [10.sup.6] pores/[cm.sup.3]. The increase in PD was due to the fact that as the SP rose, the amount of gas dissolving into the polymer matrix increased (48). This increase in gas, as mentioned earlier, induced more nucleation sites, producing an increase in PD. Furthermore, it can be seen that the average pore size obtained was once again similar to the average size of the NaCl particles used to fabricate the scaffold.
TABLE 4. Effects of saturation pressure and NaCl/polymer mass ratio on
the scaffold average pore size ([mu]m).

            NaCl/polymer mass ratio = 5  NaCl/polymer mass ratio = 20

Saturation   Saturation    Saturation     Saturation    Saturation
 pressure   time = 72 hr  time = 24 hr   time = 72 hr  time = 24 hr
  (MPa)

  4.14        202.6238      201.1756       199.3859      201.1156
  5.52        188.2775      186.5818       182.8463      177.6908

TABLE 5. Effects of saturation pressure and NaCl/polymer mass ratio on
the scaffold pore density (pores/[cm.sup.3]).

                                NaCl/polymer mass ratio = 5
Saturation pressure  Saturation time = 72 hr  Saturation time = 24 hr
        (MPa)

        4.14           1.6851 x [10.sup.6]      1.5075 x [10.sup.6]
        5.52           2.8590 x [10.sup.6]      3.0418 x [10.sup.6]

                                 NaCl/polymer mass ratio = 20

Saturation pressure  Saturation time = 72 hr  Saturation time = 24 hr
        (MPa)

        4.14           2.8691 x [10.sup.6]      3.3420 x [10.sup.6]
        5.52           4.7445 x [10.sup.6]      5.7076 x [10.sup.6]


Effects of the Processing Parameters on the Young's Modulus in Compression of the Scaffold

Compressive tests were performed to evaluate the mechanical properties of the scaffold. Figure 6 depicts the effects of the saturation time and the NaCl/PMR on the Young's modulus in compression of the scaffold using a SP of 5.52 MPa. The figure suggests that the saturation time had little effect on the Young's modulus when the saturation period was extended from 24 to 72 hr. It can also be observed that the effect of the saturation time on the Young's modulus in compression decreased as the NaCl/PMR increased. Figures 6 and 7 also demonstrate that as the NaCl/PMR was increased, the Young's modulus in compression of the scaffold decreased. For a NaCl/ PMR of 5, the Young's modulus in compression of the scaffold decreased from 0.60 to 0.38 MPa as the saturation time was extended from 12 to 72 hr. For a NaCl/ PMR of 20, the Young's modulus in compression of the scaffold ranged from 0.22 to 0.18 as the saturation time was increased from 12 to 72 hr. The fact that Young's modulus underwent a decrease due to the extension of the saturation period from 12 to 24 hr can be explained by the slight decrease in density and increase in porosity produced by the higher amount of gas that dissolved into the polymer matrix. On the other hand, the decrease in Young's modulus in compression of the scaffold due to the increase in the NaCl/PMR was due to a reduction in the amount of polymer present in the matrix and an increase in the scaffold's porosity, which is consistent with evidence in the corresponding literature (36, 45). A decrease in the amount of polymer in the scaffold suggested that less material was available to form the walls of the pore inside the scaffold, thereby compromising the ability of the scaffold to support a greater load.

[FIGURE 6 OMITTED]

[FIGURE 7 OMITTED]

Table 1 demonstrates that as the SP was increased, the Young's modulus in compression of the scaffold decreased at a lower NaCl/PMR. The SP had very little effect on the Young's modulus when high NaCl/PMRs were used. The decrease in Young's modulus in compression of the scaffold as the pressure was increased was due to the larger amount of gas absorbed by the polymer during the saturation period, which caused an increase in porosity and a decrease in density. The higher amount of gas also produced more nucleation sites, which were interspersed throughout the walls of the pores inside the scaffold and observed under SEM. The increase in nucleation sites, in turn, weakened the matrix.

CONCLUSIONS

In this article, PLGA 85/15 scaffolds made of NaCl/ PMRs of 5, 10, 15, and 20 were manufactured. A parametric study was conducted and showed that all NaCl/ PMRs used at different SPs and saturation times were successful at producing scaffolds that are promising for the development of open pore scaffolds for use in tissue engineering applications. These scaffolds had different densities, porosities, average pore sizes, pore densities, and Young's modulus in compression depending on the processing parameters used to manufacture them.

It was found that varying the saturation time, which usually affects the matrix properties when a pure polymer is used in gas foaming, had little effect in this gas foaming/salt leaching technique. Altering the SP, however, had a more significant effect on the scaffold's physical properties than changing the saturation time, but the effect was once again not as high as if a pure polymer had been used. As the SP was raised, the density, the average pore size, and Young's modulus in compression decreased slightly, whereas the porosity and PD increased. The parameter that had the most significant impact on the scaffold's properties was the NaCl/PMR. An increase in the NaCl/PMR resulted in reduced density and Young's modulus in compression, and increased porosity and PD, whereas the average pore size was constant. The pore size was found to be equal to the size of the NaCl particles used, regardless of changes in the other processing parameters. The only parameter that proved to be somewhat of an exception to this rule was the SP, which only exhibited very small effects; it was, therefore, concluded that the average pore size can be modified by either increasing or decreasing the size of the NaCl particles used.

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Josee K. Perron, (1) Hani E. Naguib, (2) Joseph Daka, (3) Attar Chawla (3)

(1) Department of Mechanical Engineering, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

(2) Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada M5S 3G8

(3) Medical Devices Bureau and Therapeutic Products Directorate, Health Canada, Ottawa, Ontario, Canada

Correspondence to: Hani E. Naguib; e-mail: naguib@mie.utoronto.ca

Contract grant sponsor: Natural Sciences and Engineering Research Council of Canada (NSERC).

DOI 10.1002/pen.21443
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Date:Oct 1, 2009
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Biodegradable nanosize particles of poly(L,L-lactide)-b-poly(ethylene glycol)-b-poly(L,L-lactide).
Poly(4-hydroxyphenylacetic acid): a new material for immobilization of biomolecules.
Rheological study of aqueous dispersions of in situ gelable thermosensitive polymer nanogels.
Effects of solvent, film thickness, and hydrogen bonding on surface-relief gratings.
Synthesis and characterization of open-cell foams for sound absorption with rotational molding method.

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