Development, characterization and clinical use of a biodegradable composite scaffold for bone engineering in oro-maxillo-facial surgery

Abstract

We have developed a biodegradable composite scaffold for bone tissue engineering applications with a pore size and interconnecting macroporosity similar to those of human trabecular bone. The scaffold is fabricated by a process of particle leaching and phase inversion from poly(lactideco-glycolide) (PLGA) and two calcium phosphate (CaP) phases both of which are resorbable by osteoclasts; the first a particulate within the polymer structure and the second a thin ubiquitous coating. The 3-5 μm thick osteoconductive surface CaP abrogates the putative foreign body giant cell response to the underlying polymer, while the internal CaP phase provides dimensional stability in an otherwise highly compliant structure. The scaffold may be used as a biomaterial alone, as a carrier for cells or a three-phase drug delivery device. Due to the highly interconnected macroporosity ranging from 81% to 91%, with macropores of 0.8∼1.8 mm, and an ability to wick up blood, the scaffold acts as both a clot-retention device and an osteoconductive support for host bone growth. As a cell delivery vehicle, the scaffold can be first seeded with human mesenchymal cells which can then contribute to bone formation in orthotopic implantation sites, as we show in immune-compromised animal hosts. We have also employed this scaffold in both lithomorph and particulate forms in human patients to maintain alveolar bone height following tooth extraction, and augment alveolar bone height through standard sinus lift approaches. We provide a clinical case report of both of these applications; and we show that the scaffold served to regenerate sufficient bone tissue in the wound site to provide a sound foundation for dental implant placement. At the time of writing, such implants have been in occlusal function for periods of up to 3 years in sites regenerated through the use of the scaffold.

Keywords: biodegradable; bone regeneration; cell delivery; clinical; clot retention; composite; extraction socket; osteoconduction; scaffold; sinus lift.

Figure 1

(A) shows the PLGA scaffolds made of PLGA IV 1.13, PLGA concentration 12.5% and (left) dry control, (middle) wet control, (right) scaffold incubated with fibroblasts for 3 weeks. The PLGA scaffold was contracted by fibroblasts after incubation for 3 weeks. (B) shows the same polymer with a calcium phosphate particulate inclusion phase [CaP/PLGA ratio 2:1]: (left) dry control, (middle) wet control, (right) scaffold incubated with fibroblasts for 3 weeks. The CaP/PLGA composite scaffold retained its original shape in the presence of cultured cells. )A + B from reference Guan & Davies.2) (C) Compressive Modulus of uncoated and coated scaffold. Mean ± SD. Data courtesy of Limin Guan.

Figure 2

Graph illustrating the percentage scaffold surface contacted by foreign body giant cells (FBGC) over time. The calcium phosphate coating is clearly shown to significantly decrease the number of FBGC at all time points. Data is mean ± standard deviation. n = 3 for each time point. From Lickorish et al.

Figure 3

Human umbilical cord perivascular cells (HUCPVCs) (A) were added to scaffold (B) and seeded by mixing in a small conical tube (C). The cellseeded scaffold was then implanted in a femoral osteotomy created in the distal femur of a nude rat (D). On biopsy of the implant site 30 days later, and labeling the preparation with a HuN (an anti-human nuclear antibody), some of the osteocytes within the reparative bone matrix were seen to be HuN positive (E), while the negative control (F) showed no labeling.

Figure 4

(A) Surgical site showing longitudinal fracture along the root of the second premolar and bone loss on the buccal aspect of all sockets. (B) Both upper right premolars were extracted with minimal trauma to the alveolar bone and the sockets were immediately grafted with two cylinders of OsteoScaf™ (3 × 10 mm). (C) Radiograph after 14 months of OsteoScaf™ grafting. The patient was fully rehabilitated with prosthetic crowns installed over titanium dental implants. (D) Clinical follow-up 2 years after the treatment was completed.

Figure 5

(A) Radiograph showing a severely resorbed alveolar ridge (2 mm in the 15 area [white arrows]) with extensive pneumatization of the right maxillary sinus. (B) Photograph, taken at the time of surgery, showing the OsteoScaf™ immediately after the sinus lift and grafting procedure. The sinus was filled in with particles of OsteoScaf™ (2–8 mm in size), which were loosely packed to maintain the material's interconnected porosity. (C) A radiograph taken immediately after dental implant placement (180 days after OsteoScaf™ grafting) shows the considerable gain in bone height, which was sufficient to allow for primary stabilization of the implants. (D) Clinical follow-up of almost 2 years after completion of the treatment.