Biomaterials-aided mandibular reconstruction using in vivo bioreactors.

Large mandibular defects are clinically challenging to reconstruct due to the complex anatomy of the jaw and the limited availability of appropriate tissue for repair. We envision leveraging current advances in fabrication and biomaterials to create implantable devices that generate bone within the patients themselves suitable for their own specific anatomical pathology. The in vivo bioreactor strategy facilitates the generation of large autologous vascularized bony tissue of customized geometry without the addition of exogenous growth factors or cells. To translate this technology, we investigated its success in reconstructing a mandibular defect of physiologically relevant size in sheep. We fabricated and implanted 3D-printed in vivo bioreactors against rib periosteum and utilized biomaterial-based space maintenance to preserve the native anatomical mandibular structure in the defect site before reconstruction. Nine weeks after bioreactor implantation, the ovine mandibles were repaired with the autologous bony tissue generated from the in vivo bioreactors. We evaluated tissues generated in bioreactors by radiographic, histological, mechanical, and biomolecular assays and repaired mandibles by radiographic and histological assays. Biomaterial-aided mandibular reconstruction was successful in a large superior marginal defect in five of six (83%) sheep. Given that these studies utilized clinically available biomaterials, such as bone cement and ceramic particles, this strategy is designed for rapid human translation to improve outcomes in patients with large mandibular defects.

Is Reconstruction of Large Mandibular Defects Using Bioengineering Materials Effective?

PURPOSE: Clinical tissue engineering has revolutionized surgery by improving surgical efficiency and decreasing the risks associated with traditional bone graft procurement techniques. Compared with autogenous bone grafts, composite tissue-engineered grafts fulfill the principles of osteoconduction, osteoinduction, and osteogenesis and provide adequate bone volume for maxillofacial reconstruction with less morbidity. The present study aimed to demonstrate the effectiveness, as defined by our success criteria, of a composite tissue-engineered bone graft in the reconstruction of mandibular defects. PATIENTS AND METHODS: We implemented a retrospective case series and enrolled a sample of patients with mandibular defects that had been reconstructed using allogeneic bone combined with recombinant human bone morphogenic protein-2 and bone marrow aspirate concentrate at our institution during a 5-year period. The success criteria were as follows: 1) bone union, defined as a homogenous radiopaque pattern continuous with native bone without mandibular mobility; and 2) volume of grafted bone adequate for implant placement, defined as at least 1.0 cm (height) by 0.8 cm (width). Clinical examinations and computed tomography scans were performed at 6 months postoperatively. Descriptive statistics were computed for each variable. RESULTS: From 2014 to 2019, tissue engineering reconstruction was used in 31 patients with and 3 patients without mandibular continuity defects, for a total of 34 patients. The median follow-up was 6 months. The mean length of the continuity defects was 5.5 cm (range, 1.0 to 12.5). Of the 30 patients with mandibular continuity defects, 27 achieved success according to our criteria, with an average gained height of 2.12 ± 0.64 cm and width of 1.53 ± 0.46 cm. Of the 34 patients, 1 was lost to follow-up, and treatment failed in 3 patients. CONCLUSIONS: Although the use of autogenous graft remains the reference standard, the evolving science behind clinical tissue engineering has resulted in an effective treatment modality for complex head and neck defects with less morbidity and graft material equal to that of autogenous bone.

Invasive Cutaneous Facial Mucormycosis in a Trauma Patient.

Mucormycosis, also known as zygomycosis, is an aggressive infection caused by a ubiquitous group of molds known as mucormycetes and is often associated with immune suppression or trauma among immunocompetent populations. We present the case of a 19-year-old woman who was involved in a motor vehicle accident in whom rapidly progressive invasive cutaneous facial mucormycosis subsequently developed. The diagnosis, treatment options, and incidence of this disease process are discussed in the context of trauma.

Immediate Transoral Allogeneic Bone Grafting for Large Mandibular Defects. Less Morbidity, More Bone. A Paradigm in Benign Tumor Mandibular Reconstruction?

PURPOSE: Reconstruction of hard tissue continuity defects caused by ablative tumor surgery has been traditionally reconstructed with autogenous bone grafts or microvascular free flaps. Although results have been predictable from these 2 methods of reconstruction, the morbidity associated with bone harvest is quite serious for the patient. Predictable results have been obtained with using a combination of 100% cadaver bone, bone marrow aspirate concentrate (BMAC), and recombinant human bone morphogenic protein in immediate reconstruction for benign tumor extirpations through the extraoral approach. In light of these successful outcomes, the same combination was evaluated with an intraoral approach. This study evaluated the success of immediate mandibular reconstruction through the intraoral approach without any autogenous bone harvesting. PATIENTS AND METHODS: The aim of this retrospective study was to share the authors' experience with the use of 100% allogeneic bone in combination with bone morphogenic protein and BMAC through the transoral approach for immediate reconstruction of continuity defects that resulted from benign tumor surgery. A retrospective chart review was performed of all patients undergoing bone graft reconstruction at the University of Texas Health Sciences Center at Houston (UTHealth) Department of Oral and Maxillofacial Surgery from December 2014 through January 2016. Inclusion criteria were biopsy-proven benign tumors, American Society of Anesthesiologists I or II health status, and adequate intraoral soft tissue for primary closure determined during initial consultation. RESULTS: Five patients who underwent this procedure at the UTHealth Department of Oral and Maxillofacial Surgery from December 2014 through January 2016 are presented. The success rate was 100%. All patients showed excellent bone quality clinically and radiographically for endosseous dental implant placement. With the transoral approach and no autogenous bone harvesting, the average operating time was 3.4 hours and the hospital stay was 2.4 days. CONCLUSIONS: Composite allogeneic tissue engineering is an effective and predictable technique for immediate reconstruction of continuity defects from ablative benign tumor surgery. Overall, there was no donor site morbidity, the intraoperative time was shorter, there were fewer admission days, and total costs overall were lower compared with traditional methods.

Effects of antibiotic physicochemical properties on their release kinetics from biodegradable polymer microparticles.

PURPOSE: This study investigated the effects of the physicochemical properties of antibiotics on the morphology, loading efficiency, size, release kinetics, and antibiotic efficacy of loaded poly(DL-lactic-co-glycolic acid) (PLGA) microparticles (MPs) at different loading percentages. METHODS: Cefazolin, ciprofloxacin, clindamycin, colistin, doxycycline, and vancomycin were loaded at 10 and 20 wt% into PLGA MPs using a water-in-oil-in water double emulsion fabrication protocol. Microparticle morphology, size, loading efficiency, release kinetics, and antibiotic efficacy were assessed. RESULTS: The results from this study demonstrate that the chemical nature of loaded antibiotics, especially charge and molecular weight, influence the incorporation into and release of antibiotics from PLGA MPs. Drugs with molecular weights less than 600 Da displayed biphasic release while those with molecular weights greater than 1,000 Da displayed triphasic release kinetics. Large molecular weight drugs also had a longer delay before release than smaller molecular weight drugs. The negatively charged antibiotic cefazolin had lower loading efficiency than positively charged antibiotics. Microparticle size appeared to be mainly controlled by fabrication parameters, and partition and solubility coefficients did not appear to have an obvious effect on loading efficiency or release. Released antibiotics maintained their efficacy against susceptible strains over the duration of release. Duration of release varied between 17 and 49 days based on the type of antibiotic loaded. CONCLUSIONS: The data from this study indicate that the chemical nature of antibiotics affects properties of antibiotic-loaded PLGA MPs and allows for general prediction of loading and release kinetics.

Repair of complex ovine segmental mandibulectomy utilizing customized tissue engineered bony flaps.

Craniofacial defects require a treatment approach that provides both robust tissues to withstand the forces of mastication and high geometric fidelity that allows restoration of facial architecture. When the surrounding soft tissue is compromised either through lack of quantity (insufficient soft tissue to enclose a graft) or quality (insufficient vascularity or inducible cells), a vascularized construct is needed for reconstruction. Tissue engineering using customized 3D printed bioreactors enables the generation of mechanically robust, vascularized bony tissues of the desired geometry. While this approach has been shown to be effective when utilized for reconstruction of non-load bearing ovine angular defects and partial segmental defects, the two-stage approach to mandibular reconstruction requires testing in a large, load-bearing defect. In this study, 5 sheep underwent bioreactor implantation and the creation of a load-bearing mandibular defect. Two bioreactor geometries were tested: a larger complex bioreactor with a central groove, and a smaller rectangular bioreactor that were filled with a mix of xenograft and autograft (initial bone volume/total volume BV/TV of 31.8 ± 1.6%). At transfer, the tissues generated within large and small bioreactors were composed of a mix of lamellar and woven bone and had BV/TV of 55.3 ± 2.6% and 59.2 ± 6.3%, respectively. After transfer of the large bioreactors to the mandibular defect, the bioreactor tissues continued to remodel, reaching a final BV/TV of 64.5 ± 6.2%. Despite recalcitrant infections, viable osteoblasts were seen within the transferred tissues to the mandibular site at the end of the study, suggesting that a vascularized customized bony flap is a potentially effective reconstructive strategy when combined with an optimal stabilization strategy and local antibiotic delivery prior to development of a deep-seated infection.

New method for analysis of facial growth in a pediatric reconstructed mandible.

INTRODUCTION: The aim of this article was to present a new method of analysis for the assessment of facial growth and morphology after surgical resection of the mandible in a growing patient. METHODS: This was a 2-year longitudinal study of facial growth in a child who had undergone segmental resection of the mandible with immediate reconstruction as a treatment for juvenile aggressive fibromatosis. Three-dimensional digital stereo-photogrammteric cameras were used for image acquisition at several follow-up intervals: immediate, 6 months, and 2 years postresection. After processing and superimposition, shell-to-shell deviation maps were used for the analysis of the facial growth pattern and its deviation from normal growth. The changes were seen as mean surface changes and color maps. An average constructed female face from a previous study was used as a reference for a normal growth pattern. RESULTS: The patient showed significant growth during this period. Positive changes took place around the nose, lateral brow area, and lower lip and chin, whereas negative changes were evident at the lower lips and cheeks area. An increase in the vertical dimension of the face at the chin region was also seen prominently. CONCLUSIONS: Three-dimensional digital stereo-photogrammetry can be used as an objective, noninvasive method for quantifying and monitoring facial growth and its abnormalities.

Knee orthopedics as a template for the temporomandibular joint.

Although the knee joint and temporomandibular joint (TMJ) experience similar incidence of cartilage ailments, the knee orthopedics field has greater funding and more effective end-stage treatment options. Translational research has resulted in the development of tissue-engineered products for knee cartilage repair, but the same is not true for TMJ cartilages. Here, we examine the anatomy and pathology of the joints, compare current treatments and products for cartilage afflictions, and explore ways to accelerate the TMJ field. We examine disparities, such as a 6-fold higher article count and 2,000-fold higher total joint replacement frequency in the knee compared to the TMJ, despite similarities in osteoarthritis incidence. Using knee orthopedics as a template, basic and translational research will drive the development and implementation of clinical products for the TMJ. With more funding opportunities, training programs, and federal guidance, millions of people afflicted with TMJ disorders could benefit from novel, life-changing therapeutics.

Bilayered, peptide-biofunctionalized hydrogels for in vivo osteochondral tissue repair.

Osteochondral defects present a unique clinical challenge due to their combination of phenotypically distinct cartilage and bone, which require specific, stratified biochemical cues for tissue regeneration. Furthermore, the articular cartilage exhibits significantly worse regeneration than bone due to its largely acellular and avascular nature, prompting significant demand for regenerative therapies. To address these clinical challenges, we have developed a bilayered, modular hydrogel system that enables the click functionalization of cartilage- and bone-specific biochemical cues to each layer. In this system, the crosslinker poly(glycolic acid)-poly(ethylene glycol)-poly(glycolic acid)-di(but-2-yne-1,4-dithiol) (PdBT) was click conjugated with either a cartilage- or bone-specific peptide sequence of interest, and then mixed with a suspension of thermoresponsive polymer and mesenchymal stem cells (MSCs) to generate tissue-specific, cell-encapsulated hydrogel layers targeting the cartilage or bone. We implanted bilayered hydrogels in rabbit femoral condyle defects and investigated the effects of tissue-specific peptide presentation and cell encapsulation on osteochondral tissue repair. After 12 weeks implantation, hydrogels with a chondrogenic peptide sequence produced higher histological measures of overall defect filling, cartilage surface regularity, glycosaminoglycan (GAG)/cell content of neocartilage and adjacent cartilage, and bone filling and bonding compared to non-chondrogenic hydrogels. Furthermore, MSC encapsulation promoted greater histological measures of overall defect filling, cartilage thickness, GAG/cell content of neocartilage, and bone filling. Our results establish the utility of this click functionalized hydrogel system for in vivo repair of the osteochondral unit. STATEMENT OF SIGNIFICANCE: Osteochondral repair requires mimicry of both cartilage- and bone-specific biochemical cues, which are highly distinct. While traditional constructs for osteochondral repair have mimicked gross compositional differences between the cartilage and bone in mineral content, mechanical properties, proteins, or cell types, few constructs have recapitulated the specific biochemical cues responsible for the differential development of cartilage and bone. In this study, click biofunctionalized, bilayered hydrogels produced stratified presentation of developmentally inspired peptide sequences for chondrogenesis and osteogenesis. This work represents, to the authors' knowledge, the first application of bioconjugation chemistry for the simultaneous repair of bone and cartilage tissue. The conjugation of tissue-specific peptide sequences successfully promoted development of both cartilage and bone tissues in vivo.

An Ovine Model of In Vivo Bioreactor-Based Bone Generation.

The generation of vascularized mineralized tissues of complex geometry without the use of extrinsic growth factors or exogenous cells requires a large animal model to recapitulate the challenges seen in the clinic. The proposed versatile ovine model can be utilized to investigate the use of a customized bioreactor to generate mineralized tissue, matching the size and shape of a defect before transfer to and integration within another site. The protocol results in bioreactors that can be harvested for investigation of the effects of different biomaterials for the generation of bone or to generate tissues appropriate for repair of bony defects; this protocol focuses on reconstruction of the mandible but could be modified for orthopedic applications. The bioreactor packing material can be altered, allowing for the study of various commercially available or novel graft materials. The surgical procedure requires ∼1.5 h to implant four bioreactors adjacent to rib periosteum. After 9 weeks, the harvest of the bioreactor tissue takes approximately 1 h. If creating a craniofacial defect, an additional 2 h should be taken for mandibular defect creation and 2 to 3 h for the reconstruction. Sheep that have undergone reconstruction are typically euthanized after 12 weeks to allow for evaluation of transferred tissues. In this protocol, we discuss the necessary steps to ensure the reproducibility and analytical techniques to assess bone regeneration such as microcomputed tomography, mechanical analysis, and histology. Impact statement Bone grafting is a frequent procedure in the fields of orthopedics, otolaryngology, and oral and maxillofacial surgery. Generating customized, vascularized, and mechanically robust bony tissues while eliminating common complications such as donor site morbidity with autograft harvest or lack of suitable mechanical properties with commercially available synthetic graft would greatly improve the lives of patients. A large animal model is necessary to generate tissues of clinically relevant geometries. In this article, a reproducible ovine model of in vivo bioreactor technology toward customized bone generation is presented with broad application to tissue engineering and regenerative medicine.

A Rabbit Femoral Condyle Defect Model for Assessment of Osteochondral Tissue Regeneration.

Osteochondral tissue repair represents a common clinical need, with multiple approaches in tissue engineering and regenerative medicine being investigated for the repair of defects of articular cartilage and subchondral bone. A full thickness rabbit femoral condyle defect is a clinically relevant model of an articulating and load bearing joint surface for the investigation of osteochondral tissue repair by various cell-, biomolecule-, and biomaterial-based implants. In this protocol, we describe the methodology and 1.5- to 2-h surgical procedure for the generation of a reproducible, full thickness defect for construct implantation in the rabbit medial femoral condyle. Furthermore, we describe a step-by-step procedure for osteochondral tissue collection and the assessment of tissue formation using standardized histological, radiological, mechanical, and biochemical analytical techniques. This protocol illustrates the critical steps for reproducibility and minimally invasive surgery as well as applications to evaluate the efficacy of cartilage and bone tissue engineering implants, with emphasis on the usage of histological and radiological measures of tissue growth. Impact statement Although multiple surgical techniques have been developed for the treatment of osteochondral defects, repairing the tissues to their original state remains an unmet need. Such limitations have thus prompted the development of various constructs for osteochondral tissue regeneration. An in vivo model that is both clinically relevant and economically practical is necessary to evaluate the efficacy of different tissue engineered constructs. In this article, we present a full thickness rabbit femoral condyle defect model and describe the analytical techniques to assess the regeneration of osteochondral tissue.

Localized mandibular infection affects remote in vivo bioreactor bone generation.

Mandibular reconstruction requires functional and aesthetic repair and is further complicated by contamination from oral and skin flora. Antibiotic-releasing porous space maintainers have been developed for the local release of vancomycin and to promote soft tissue attachment. In this study, mandibular defects in six sheep were inoculated with 106 colony forming units of Staphylococcus aureus; three sheep were implanted with unloaded porous space maintainers and three sheep were implanted with vancomycin-loaded space maintainers within the defect site. During the same surgery, 3D-printed in vivo bioreactors containing autograft or xenograft were implanted adjacent to rib periosteum. After 9 weeks, animals were euthanized, and tissues were analyzed. Antibiotic-loaded space maintainers were able to prevent dehiscence of soft tissue overlying the space maintainer, reduce local inflammatory cells, eliminate the persistence of pathogens, and prevent the increase in mandibular size compared to unloaded space maintainers in this sheep model. Animals with an untreated mandibular infection formed bony tissues with greater density and maturity within the distal bioreactors. Additionally, tissues grown in autograft-filled bioreactors had higher compressive moduli and higher maximum screw pull-out forces than xenograft-filled bioreactors. In summary, we demonstrated that antibiotic-releasing space maintainers are an innovative approach to preserve a robust soft tissue pocket while clearing infection, and that local infections can increase local and remote bone growth.

Bone Reconstruction Planning Using Computer Technology for Surgical Management of Severe Maxillomandibular Atrophy.

Digital imaging technology and refined software programs have significantly improved a clinician's ability to assess and evaluate anatomic structures and quantify both defect size and required graft volume. This article summarizes the computed tomography-based technology used in these applications to illustrate their current use as exemplified by computer-assisted planning and treatment of severe maxillofacial atrophy treated using both interpositional and mesh-onlay grafting methodology.

Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model.

This study investigated the effects of dual delivery of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) for bone regeneration in a rat cranial critical size defect. Four groups of scaffolds were generated with VEGF (12 microg), BMP-2 (2 mug), both VEGF (12 microg) and BMP-2 (2 microg), or no growth factor released from gelatin microparticles incorporated within the scaffold pores. These scaffolds were implanted within an 8 mm rat cranial critical size defect (n=8-9 for each group). At 4 and 12 weeks, implants were retrieved and evaluated by microcomputed tomography (microCT) and histological scoring analysis. Additionally, 4 week animals were perfused with a radiopaque material to visualize and quantify blood vessel formation. Histological analysis revealed that for all groups at 4 weeks, a majority of the porous scaffold volume was filled with vascularized fibrous tissue; however, bone formation appeared most abundant in the dual release group at this time. At 12 weeks, both dual release and BMP-2 groups showed large amounts of bone formation within the scaffold pores and along the outer surfaces of the scaffold; osteoid secretion and mineralization were apparent, and new bone was often in close or direct contact with the scaffold interface. MicroCT results showed no significant difference among groups for blood vessel formation at 4 weeks (<4% blood vessel volume); however, the dual release group showed significantly higher bone formation (16.1+/-9.2% bone volume) than other groups at this time. At 12 weeks, dual release and BMP-2 groups exhibited significantly higher bone formation (39.7+/-14.1% and 37.4+/-18.8% bone volume, respectively) than either the VEGF group or blank scaffolds (6.3+/-4.8% and 7.8+/-7.1% bone volume, respectively). This work indicates a synergistic effect of the dual delivery of VEGF and BMP-2 on bone formation at 4 weeks and suggests an interplay between these growth factors for early bone regeneration. For the doses investigated, the results show that the addition of VEGF does not affect the amount of bone formation achieved by BMP-2 at 12 weeks; however, they also indicate that delivery of both growth factors may enhance bone bridging and union of the critical size defect compared to delivery of BMP-2 alone.

Tissue engineering toward temporomandibular joint disc regeneration.

Treatments for temporomandibular joint (TMJ) disc thinning and perforation, conditions prevalent in TMJ pathologies, are palliative but not reparative. To address this, scaffold-free tissue-engineered implants were created using allogeneic, passaged costal chondrocytes. A combination of compressive and bioactive stimulation regimens produced implants with mechanical properties akin to those of the native disc. Efficacy in repairing disc thinning was examined in minipigs. Compared to empty controls, treatment with tissue-engineered implants restored disc integrity by inducing 4.4 times more complete defect closure, formed 3.4-fold stiffer repair tissue, and promoted 3.2-fold stiffer intralaminar fusion. The osteoarthritis score (indicative of degenerative changes) of the untreated group was 3.0-fold of the implant-treated group. This tissue engineering strategy paves the way for developing tissue-engineered implants as clinical treatments for TMJ disc thinning.

A composite critical-size rabbit mandibular defect for evaluation of craniofacial tissue regeneration.

Translational biomaterials targeted toward the regeneration of large bone defects in the mandible require a preclinical model that accurately recapitulates the regenerative challenges present in humans. Computational modeling and in vitro assays do not fully replicate the in vivo environment. Consequently, in vivo models can have specific applications such as those of the mandibular angle defect, which is used to investigate bone regeneration in a nonload-bearing area, and the inferior border mandibular defect, which is a model for composite bone and nerve regeneration, with both models avoiding involvement of soft tissue or teeth. In this protocol, we describe a reproducible load-bearing critical-size composite tissue defect comprising loss of soft tissue, bone and tooth in the mandible of a rabbit. We have previously used this procedure to investigate bone regeneration, vascularization and infection prevention in response to new biomaterial formulations for craniofacial tissue engineering applications. This surgical approach can be adapted to investigate models such as that of regeneration in the context of osteoporosis or irradiation. The procedure can be performed by researchers with basic surgical skills such as dissection and suturing. The procedure takes 1.5-2 h, with ∼2 h of immediate postoperative care, and animals should be monitored daily for the remainder of the study. For bone tissue engineering applications, tissue collection typically occurs 12 weeks after surgery. In this protocol, we will present the necessary steps to ensure reproducibility; tips to minimize complications during and after surgery; and analytical techniques for assessing soft tissue, bone and vessel regeneration by gross evaluation, microcomputed tomography (microCT) and histology.

Reconstruction of large mandibular defects using autologous tissues generated from in vivo bioreactors.

Reconstruction of large mandibular defects is clinically challenging due to the need for donor tissue of appropriate shape and volume to facilitate high fidelity repair. In order to generate large vascularized tissues of custom geometry, bioreactors were implanted against the rib periosteum of 3-4year-old sheep for nine weeks. Bioreactors were filled with either morcellized autologous bone, synthetic ceramic particles, or a combination thereof. Tissues generated within synthetic graft-filled bioreactors were transferred into a large right-sided mandibular angle defect as either avascular grafts (n=3) or vascularized free flaps (n=3). After twelve additional weeks, reconstructed mandibular angles were harvested and compared to contralateral control angles. Per histologic and radiologic evaluation, a greater amount of mineralized tissue was generated in bioreactors filled with autologous graft although the quality of viable bone was not significantly different between groups. Genetic analyses of soft tissue surrounding bioreactor-generated tissues demonstrated similar early and late stage osteogenic biomarker expression (Runx2 and Osteocalcin) between the bioreactors and rib periosteum. Although no significant differences between the height of reconstructed and control mandibular angles were observed, the reconstructed mandibles had decreased bone volume. There were no differences between mandibles reconstructed with bioreactor-generated tissues transferred as flaps or grafts. Tissues used for mandibular reconstruction demonstrated integration with native bone as well as evidence of remodeling. In this study, we have demonstrated that synthetic scaffolds are sufficient to generate large volumes of mineralized tissue in an in vivo bioreactor for mandibular reconstruction. STATEMENT OF SIGNIFICANCE: A significant clinical challenge in craniofacial surgery is the reconstruction of large mandibular defects. In this work, we demonstrated that vascularized tissues of large volume and custom geometry can be generated from in vivo bioreactors implanted against the rib periosteum in an ovine model. The effects of different bioreactor scaffold material on tissue ingrowth were measured. To minimize donor site morbidity, tissues generated from bioreactors filled with synthetic graft were transferred as either vascularized free flaps or avascular grafts to a large mandibular defect. It was demonstrated that synthetic graft in an in vivo bioreactor is sufficient to produce free tissue bone flaps capable of integrating with native tissues when transferred to a large mandibular defect in an ovine model.

Polymer-Based Local Antibiotic Delivery for Prevention of Polymicrobial Infection in Contaminated Mandibular Implants.

Antibiotic-releasing porous poly(methyl methacrylate) (PMMA) space maintainers, comprising PMMA with an aqueous porogen and a poly(DL-lactic-co-glycolic acid) (PLGA) antibiotic carrier, have been developed to facilitate local delivery of antibiotics and tissue integration. In this study, clindamycin-loaded space maintainers were used to investigate the effects of antibiotic release kinetics and dose upon bacterial clearance and bone and soft tissue healing in a pathogen-contaminated rabbit mandibular defect. Three formulations were fabricated for either high dose burst release (7 days) or with PLGA microparticles for extended release (28 days) at high and low dose. Although inoculated bacteria were not recovered from any specimens, the burst release formulation showed less inflammation and fibrous capsule formation and more bone formation close to the implant than the low dose extended release formulation by histologic analysis. These results suggest that local antibiotic release kinetics and dose affect soft and hard tissue healing independent from its ability to clear bacteria.