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. Author manuscript; available in PMC: 2013 Apr 1.
Published in final edited form as: J Biomed Mater Res A. 2012 Jan 12;100(4):827–833. doi: 10.1002/jbm.a.34016

In situ Formation of Porous Space Maintainers in a Composite Tissue Defect

Patrick P Spicer 1, James D Kretlow 1, Allan M Henslee 1, Meng Shi 1, Simon Young 2, Nagi Demian 2, John A Jansen 3, Mark E Wong 2, Antonios G Mikos 1, F Kurtis Kasper 1,*
PMCID: PMC3288442  NIHMSID: NIHMS349978  PMID: 22241726

Abstract

Reconstruction of composite defects involving bone and soft tissue presents a significant clinical challenge. In the craniofacial complex, reconstruction of the soft and hard tissues is critical for both functional and aesthetic outcomes. Constructs for space maintenance provide a template for soft tissue regeneration, priming the wound bed for a definitive repair of the bone tissue with greater success. However, materials used clinically for space maintenance are subject to poor soft tissue integration, which can result in wound dehiscence. Porous materials in space maintenance applications have been previously shown to support soft tissue integration and to allow for drug release from the implant to further prepare the wound bed for definitive repair. This study evaluated solid and low porosity (16.9 ± 4.1%) polymethylmethacrylate space maintainers fabricated intraoperatively and implanted in a composite rabbit mandibular defect model for 12 weeks. The data analyses showed no difference in the solid and porous groups both histologically, evaluating the inflammatory response at the interface and within the pores of the implants, and grossly, observing the healing of soft tissue defect over the implant. These results demonstrate the potential of porous polymethylmethacrylate implants formed in situ for space maintenance in the craniofacial complex, which may have implications in the potential delivery of therapeutic drugs to prime the wound site for a definitive bone repair.

Keywords: Polymethylmethacrylate, Space maintenance, Craniofacial tissue engineering, In situ formation, Wound dehiscence

Introduction

Craniofacial defects present a complex set of injuries to repair due to the diversity of tissue form, function and type. Consequently, craniofacial trauma and tumor resections frequently result in composite defects, with greater than 90% of significant mandibular reconstructions involving an additional soft tissue defect.1 Several studies have shown that the immediate reconstruction of craniofacial defects results in improved outcomes measured both aesthetically and functionally.2-6 However, the complication rates are greater for immediate reconstructions than for secondary reconstructions.7 These complications typically involve the failure of a bone graft or the lack of viable soft tissue to support bone regeneration.7,8

Space maintenance alleviates many of these complications by allowing an alloplastic material to conserve the bony space, thereby preventing wound contracture and delaying bone regeneration within the defect until a suitable wound bed has been created. However, the implantation of bone grafts or synthetic graft materials commonly results in failure due to infection or wound dehiscence.8-11 Previous research has shown that porous materials for space maintenance or contouring lead to greater soft tissue integration and therefore decreased wound dehiscence relative to non-porous materials.12-14 For example, in a study by Sclafani et al., the use of porous polyethylene implants led to decreased extrusion in a rat subcutaneous model.14 Additionally, the skin healed more frequently after intentional exposure in the porous implants compared to solid silicone either by secondary intention or skin grafting.14 Kretlow et al. investigated the tissue response to the implantation of porous PMMA space maintainers in a rabbit composite craniofacial tissue defect.13 In this study, porous PMMA implants were fabricated by mixing PMMA bone cement with carboxymethylcellulose (CMC) gels, which created a porous structure through phase separation, as PMMA and CMC are hydrophobic and hydrophilic, respectively. Implantation of the porous PMMA constructs resulted in soft tissue healing with a reduced inflammatory response in the case of low porosity (16.9 ± 4.1%) implants as compared to those of high porosity (44.6 ± 2.1%). Additionally, in a study by Shi et al., PMMA/CMC constructs were evaluated mechanically compressively and found to have adequate properties to maintain the bony space with compressive moduli and 2.0% offset strength of 262-586 MPa and 8-20 MPa, respectively.15 However, while formulating a relationship between soft tissue healing and inflammatory response and the porosity of a space maintainer, the study by Kretlow et al. utilized prefabricated implants created in the laboratory with shape-specific molds. While prefabrication provides a controlled manner by which to evaluate eventual material parameters for scientific study, in situ polymerizable implants are important for clinical use as craniofacial defects non-uniform in shape and size. However for in situ polymerization any generated heat or unreacted monomer, as well as any variability due to intraoperative mixing, molding, and polymerization, can adversely affect the implant performance.

The present study investigates the biocompatibility of low porosity PMMA implants formed in situ as space maintainers in a rabbit composite craniofacial tissue defect. We hypothesize that low porosity space maintainers formed in situ will enhance soft tissue healing as compared to solid space maintainers formed in situ. We also hypothesize that low porosity space maintainers will not increase the inflammatory response of the hard and soft tissue surrounding the implants over solid space maintainers.

Materials and Methods

Materials

Clinical grade bone cement (SmartSet High Viscosity Bone Cement, Depuy Orthopaedics, Warsaw, IN) was used as received. U.S. Pharmacopeia grade CMC (Spectrum Chemical Manufacturing Group, Gardena, CA) was sterilized by exposure to UV light for 30 min.

Materials Preparation

Solid and porous PMMA implants were made as previously described.13,15 Briefly, CMC gels were made by dissolving sterilized CMC powder into sterile distilled water at 9 wt%. PMMA implants were prepared using the ratio (40 g of the powder phase to 18.88 g of the monomer phase of bone cement) set forth in the manufacturer's instructions and for the porous implants the CMC gel accounted for 30 wt% of the total implant. The porous implants had a porosity of 16.9 ± 4.1% and an interconnectivity of 39.7 ± 9.4%, 17.8 ± 1.2% and 13.1 ± 3.0% with a 40, 80 and 160 μm minimum interconnection size, respectively, as reported previously.13

Surgical Procedure

22 adult male New Zealand White rabbits (Myrtle's Rabbitry, Thompsons Station, TN) aged greater than 6 months for skeletal maturity were used in this study. All manipulations followed protocols approved by the Institutional Animal Care and Use Committees of Rice University and the University of Texas Health Science Center at Houston and NIH guidelines for the care and use of laboratory animals (NIH Publication #85-23 Rev. 1985) have been observed. The surgical procedure was completed as described previously.13

Briefly, anesthesia was induced with injection of a mixture of ketamine hydrochloride (40 mg/kg body weight) and xylazine hydrochloride (7.5 mg/kg body weight). The rabbits were then intubated and maintained on 2% isoflurane in oxygen. Each animal was given a preoperative dose of buprenorphine hydrochloride (0.1 mg/kg body weight) for perioperative pain control and 0.5 mL Durapen® (150,000U/mL of penicillin G benzathine and penicillin G procaine each) for perioperative antimicrobial coverage. The animals were sterilely prepped and a midline incision, 1 cm posterior to the mentum, was used to expose the inferior border of the mandible. The masseter was lifted from the buccal surface of the body of the mandible. Using a 10 mm trephine (ACE Surgical, Brockton, MA) and a surgical drill (Stryker, Kalamazoo, MI), a 10 mm bicortical defect was created. Additionally, using a 701 cutting bur, a 2-3 mm notch was created in the superior border of the defect and the overlying crown removed to create intraoral communication and a mucosal defect as shown in Figures 1A and 1B.

Figure 1.

Figure 1

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Schematic (A) and photograph (B) of defect in rabbit mandible (Scale bars indicate 10 mm and 5 mm, respectively). Photograph (C) of rabbit mandibular defect filled with a porous implant (Scale bar indicates 5 mm).

Solid implants (n=10) were prepared by mixing the liquid phase of the bone cement into the powder phase. Porous implants (n=10) were made by first mixing the powder phase (containing polymeric microparticles, benzoyl peroxide and barium sulfate) of the bone cement into the CMC gel, then mixing in the liquid phase (containing methyl methacrylate monomer and N,N-dimethyl-p-toluidine). All implants were mixed by hand until doughy and then shaped by hand to approximately fit the bone defect. The implants were placed into the bone defect approximately 5 min after initiation of polymerization (addition of liquid phase) and molded to fit once inside the defect as shown in Figure 1C.

A 6-hole 1.5 mm titanium plate (Synthes, West Chester, PA) was attached with two screws on each side of the defect to prevent iatrogenic fracture of the mandible. Finally, the wound, except the mucosal defect, which was left open to allow for continued oral communication, was closed in layers. Animals were given a postoperative intramuscular dose of ketoprofen for inflammation control. Each rabbit was extubated and closely monitored postoperatively. The animals were fed ad libitum with a diet of soft chow (Critical Care for Herbivores; Oxbow Pet Products, Murdock, NE) to reduce stress on the mandible.

Gross Observation

After 12 weeks, animals were euthanized with 1 mL of Beuthanasia-D® (390 mg/mL pentobarbital sodium and 50 mg/mL phenytoin sodium) and the hemimandible was extracted. The oral mucosa was observed grossly for complete coverage of the implant and bone. Each sample was assigned a healed or non-healed status based on this coverage, where exposure of bone or the implant was deemed non-healed and complete coverage was considered healed.

Histology

Each hemimandible was placed in 10% neutral buffered formalin for 72 hours. After fixation, each specimen was dehydrated using an ethanol gradient (70%-100%). The dehydrated samples were embedded in methylmethacrylate and three 10 μm sections were taken coronally through the center of the implant to include the mucosal defect using a microtome with an inner circular diamond blade (Leica Microsystems, Nussloch, Germany). The sections were stained with methylene blue and basic fuchsin to assess the soft tissue and hard tissue responses to the implant. The stained sections were scored by three reviewers (P.P.S., A.M.H. and F.K.K.) using a quantitative tissue-implant scoring system for the tissue-implant interface and within the pores for porous samples as shown in Table 1 and as previously described.16 Each sample received one score from a consensus of the reviewers based on the average of the three sections from the sample.

Table 1.

Histologic scoring system for implants at the implant-tissue interface as well as in the pores of porous implants.

Hard tissue response at the implant-bone interface Score
Direct bone-to-implant contact without soft interlayer 4
Remodeling lacuna with osteoblasts and/or osteoclasts at surface 3
Majority of implant is surrounded by fibrous tissue capsule 2
Unorganized fibrous tissue (majority of tissue is not arranged as capsule) 1
Inflammation marked by an abundance of inflammatory cells and poorly organized tissue 0
Hard tissue response within the pores of the scaffold
Tissue in pores is mostly bone 4
Tissue in pores consists of some bone within mature, dense fibrous tissue and/or a few inflammatory response elements 3
Tissue in pores is mostly immature fibrous tissue (with or without bone) with blood vessels and young fibroblasts invading the space with few macrophages present 2
Tissue in pores consists mostly of inflammatory cells and connective tissue components in between (with or without bone) or the majority of the pores are empty or filled with fluid 1
Tissue in pores is dense and exclusively of inflammatory type (no bone present) 0
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Statistical Analysis

Healing status based on gross observations was analyzed with Fisher's Exact Test, while histology scores, a nonparametric data set, were analyzed with the Mann Whitney-U Test. An a priori level of significance was set at α = 0.05.

Results

Surgical Procedure

All rabbits underwent surgical manipulation and recovery well. Two rabbits were replaced within the study due to complications, resulting in 22 total rabbits, with 10 rabbits included in each group for analysis. Both complications were unrelated to the surgical manipulation or implantation and involved a foot problem and an abdominal infection.

Gross Observation

Representative gross images of healed and non-healed specimens from each group are shown in Figure 2. As shown in Figure 3, 6 out of the 10 rabbits that received solid implants and 3 out of the 10 that received porous implants were considered non-healed based on the criteria described above. These results do not show significantly greater healing in the porous group (p = 0.185).

Figure 2.

Figure 2

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Photographs of the oral mucosa over the composite defect for (A) a well-healed porous implant and (B) a poorly healed, exposed solid implant after 12 weeks of implantation. The black arrow indicates implant exposure.

Figure 3.

Figure 3

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Number of implants with healed and non-healed oral mucosa for solid and porous implants after 12 weeks of implantation (n=10 for each group).

Histology

Representative histologic images from each group showing similar tissue responses for both solid and porous implants are shown in Figure 4. While the lower magnification images in Figure 4(A-D) allow for general implant assessment of the tissue response, the higher magnifications in Figure 4(E-F) illustrate the fibrous tissue present between the bone and implant. Histologic scoring, shown in Figure 5, revealed no significant difference between the solid and porous groups for the tissue-implant interface. Additionally, the scores for the tissue inside the pores for the porous group are presented in Figure 6, reflecting the presence of primarily fibrous tissue.

Figure 4.

Figure 4

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Representative images (1000 μm scale bar) from (A) the solid implant group and (B) the porous implant group with higher magnifications, highlighted in yellow, (200 μm scale bar) of each (C) and (D), respectively. Histologic scores were made using magnifications shown in images (A-D). Additional higher magnification images of (C) and (D), highlighted in yellow, are shown in (E) and (F), respectively (50 μm scale bar). The solid implant shown was scored as a 1 according to Table 1, as an unorganized fibrous capsule was present around the majority of the implant (A and C). The porous implant shown was scored as a 2 due to the presence of an organized fibrous capsule, based on the magnifications shown in (B and D). Black arrows show the titanium plate. Red arrow indicates dehiscence.

Figure 5.

Figure 5

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Histologic scores of the inflammatory response at the tissue-implant interface of solid and porous implants. There was not a significant difference between the solid and porous groups as determined by the Mann-Whitney U test.

Figure 6.

Figure 6

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Histologic scores of the tissue within the pores of the porous implants.

Discussion

Early intervention has been shown to be advantageous in the reconstruction of craniofacial defects; however, the ultimate success of a bone regeneration technique applied early after bone excision or wound debridement may be limited, given the complexity of the tissue environment, need for critical care stabilization or availability of reconstructive surgeons at that time. Consequently, temporary placement of a material to support soft tissue healing around the defect can prime the wound bed to support the success of a subsequent definitive repair. Yet, current materials fail to properly integrate with the surrounding tissue to sustain healthy soft tissue healing during implantation in such space maintenance approaches.

In a previous study, our group found that, when fabricated ex vivo, porous PMMA constructs enhanced wound healing and elicited a favorable soft tissue response compared to solid constucts.13 This approach, while a useful proof of principle, does not accurately reflect the intraoperative construct fabrication and implantation technique that would ideally be utilized to address complex craniofacial wounds. This study hypothesized that porous implants created in the operating room and formed in situ would enhance soft tissue healing over a bone defect in a composite tissue model compared to non-porous implants. Additionally, porous implants were hypothesized not to increase the inflammatory response of the surrounding tissue compared to non-porous implants, as evaluated by histology.

Porous implants showed a trend towards increased soft tissue healing of the composite defect, although differences were not statistically significant with the given sample size. This trend is consistent with previous studies using the same materials in prefabricated implants.13 This result validates the use of porous PMMA space maintainers as an alternative to solid PMMA.

Histologically, the porous implants performed similarly to the solid implants with scores that were not significantly different. This finding indicates that the in situ formation of porous space maintainers does not increase the inflammatory response of the surrounding tissue as could be postulated based on the potential for inflammatory stimuli, such as thermal energy release during polymerization or exposure to unpolymerized monomer.

The composite tissue defect used in this study separates the healing of a soft tissue defect over an implant from the inflammatory response of the tissue to the implant, which allows for study of the gross soft tissue healing over such implants. Additionally, this study perpetuates the enhancement of soft tissue healing over porous space maintainers in a clinically relevant scenario using clinically available materials, validating the process and procedure for fabricating porous space maintainers in situ. However, while separating the effects of solid and porous implants formed in situ, the presence of materials is less controlled. In the study by Kretlow et al., the CMC gel porogen was leached from the prefabricated implants prior to implantation, whereas this phase was included in the implants in the present study.13 While the effect on soft tissue to the implant could be altered by the presence of CMC, previous in vitro studies have shown that the dissolution of CMC out of the implant occurs very rapidly, thus minimizing the duration of immediate tissue contact. Moreover, while this model includes a composite defect more similar to that of craniofacial trauma or resection, the soft tissue defect is limited to the mucosal surfaces. Skin dehiscence is an important complication of craniofacial reconstruction, and further studies would be necessary to elucidate any differences between the soft tissue healing in a composite defect with a skin defect.

Previous studies have investigated the in situ polymerization of PMMA in contact with bone. Many of the studies have focused on the temperature rise and the residual monomer release from the implants, both of which have been shown to contribute to increased inflammatory responses in the tissue immediately adjacent to the PMMA implanted.17-21 Several studies have shown decreased setting temperature of porous PMMA versus solid PMMA, as there is reduced monomer per unit volume as well as a non-reacting phase acting as a heat sink.15,22 Similar to this study, where the solid and porous groups performed similarly histologically, a 14 week study by Nathanson et al. and a 12 week study by Kretlow et al. showed no difference in histological assessment of solid or porous implants at the end time point.13,23 Contrary to these studies, van Mullem et al. observed porous implants with 50 wt% of CMC gel as the porogen were surrounded by well-vascularized fibrous tissue, while solid implants had a thick fibrous capsule in a long term study of 8 and 24 months, indicating the possibility for further remodeling of the surrounding tissue in the porous implant group, which could differentiate the histological scores.24

The hypothesis that porous implants enhance tissue remodeling around the implant is supported by studies investigating the role of surface structure on tissue interfaces. These studies have shown a response dependent on surface roughness, where increased surface roughness leads to greater remodeling of the surrounding tissue.25,26 In addition, these studies indicate the possibility for greater bone remodeling for rough surfaces over smooth surfaces, as increased bone deposition is seen when cultured with osteoblast like cells and increased osteoclastic activity when cultured with macrophages.

In addition to surface characteristics, PMMA particulates play an important role in the inflammatory response, as they have been shown to increase macrophage activation and release of tumor necrosis factor-alpha, a cytokine that enhances bone resorption when produced chronically.27-30 In a study by Beck and Boger, PMMA particulate release was observed to be greater for porous PMMA than for solid PMMA.31 While these particulates may play a role in the remodeling process of the tissue surrounding the porous implants, the histological results from the present study indicate no difference, suggesting the effect of surface characteristics balances that of particulates.

In addition to effects described above regarding the advantages of porous structures for soft and hard tissue integration, interconnected porous structures increase the surface area available for drug delivery. In space maintenance, drug delivery can be used to prime the wound bed by treating any infection present.15,32 Alternatively, growth factors could be used to enhance the regeneration of soft tissue or vascularity around the implant.

While this study validates the effectiveness of porous space maintainers in a more clinically relevant model and formation process, further studies could be warranted to elucidate the effects observed. Firstly, an increase in animal numbers could be utilized to determine the significance of the mucosal healing or histological differences. As stated above, moving from prefabricated implants to those formed intraoperatively, several parameters are changed: in situ polymerization, exposure to unpolymerized monomer, and presence of the porogen, CMC. To adequately understand the effect of each of the parameters, further study would be necessary, such as investigation of a prefabricated implant from which the porogen had not been leached prior to implantation. Additionally, wound dehiscence, while more common on the mucosal surface of mandibular implants, can occur on the skin surface. The intact inferior border of the mandible does not allow for testing of this possibility, while a continuity defect of the mandible would provide such an analysis. Nevertheless, the present study supports the use of porous space maintainers for the treatment of composite tissue defects in the craniofacial region.

Conclusion

This study analyzed the effects of porous PMMA space maintainers formed in situ on the mucosal healing and long term tissue response in a rabbit composite mandibular defect model against similarly formed solid implants. The porous implants showed a trend of enhanced soft tissue healing and coverage of the implant over solid groups. Additionally, the increased surface area and presence of porogen did not elicit an extended inflammatory response over the solid implants.

Acknowledgements

This work was supported by a grant from the Armed Forces Institute of Regenerative Medicine (W81XWH-08-2- 0032). P.P.S. acknowledges support from the Robert and Janice McNair Foundation. J.D.K. acknowledges support from the Baylor College of Medicine Medical Scientist Training Program (NIH T32 GM07330), Rice Institute of Biosciences and Bioengineering's Biotechnology Training Grant (NIH T32 GM008362), and a training fellowship from the Keck Center Nanobiology Training Program of the Gulf Coast Consortia (NIH Grant No. 5 T90 DK070121-04).

Footnotes

Paper for consideration of the 2012 Society For Biomaterials Young Investigator Award (F. K. Kasper) and publication in the Journal of Biomedical Materials Research, Part A

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