James Wykes

Patient-matched scaffold guided bone regeneration (SGBR) has been poised to revolutionize the management of critical-sized bone defects due to trauma, tumors, infection, and congenital deformities. However, translation has been hampered by the focus on bioresorbable scaffolds where the rate of scaffold degradation needs to be precisely and predictably matched to the rate of new bone formation. Furthermore, resorbable ceramics and polymers require augmentation by metal plates to overcome their mechanical limitations under load. Consequently, there are no published studies using SGBR for segmental defects without metal plates, which cause stress shielding and X-ray perturbation. Even with augmentation, very few studies use animal models where the loads are comparable to humans. Segmental defects of the mandible represent one of the most challenging examples of critical-sized bone defects due to the high tensile and shear stresses encountered during mastication. The ovine mandible is an excellent model because the high and repetitive loads exceed those encountered in humans. Here, we describe the first successful long-term reconstruction of ovine segmental mandibulectomy defects using permanent, patient-matched, numerically optimized, 3D-printed, thermally toughened, plasma-treated, and selectively-laser-sintered polyetherketone gyroid scaffolds. The scaffolds house a resorbable ceramic lattice infused with a stem cell laden hydrogel and serve as an osteoinductive reservoir of calcium. Durable clinical performance and osseointegration was established in vivo and ex vivo, indicating for the first time that there is a reliable and translatable patient-matched SGBR alternative to traditional bone grafts and metal plate fixation.

Considerable research is being undertaken to develop novel biomaterials-based approaches for surgical reconstruction of bone defects. This extends to three-dimensional (3D) printed materials that provide stable, structural, and functional support in vivo . However, few preclinical models can simulate in vivo human biological conditions for clinically relevant testing. In this study we describe a novel ovine model that allows evaluation of in vivo osteogenesis via contact with bone and/or periosteum interfaced with printed polymer bioreactors loaded with biomaterial bone substitutes. The infraspinous scapular region of 14 Dorset cross sheep was exposed. Vascularized periosteum was elevated either attached to the infraspinatus muscle or separately. In both cases, the periosteum was supplied by the periosteal branch of the circumflex scapular vessels. In eight sheep, a 3D printed 4-chambered polyetheretherketone bioreactor was wrapped circumferentially in vascularized periosteum. In 6 sheep, 12 double-sided 3D printed 2-chambered polyetherketone bioreactors were secured to the underlying bone allowing direct contact with the bone on one side and periosteum on the other. Our model enabled simultaneous testing of up to 24 (12 double-sided) 10 × 10 × 5 mm bioreactors per scapula in the flat contact approach or a single 40 × 10 mm four-chambered bioreactor per scapula using the periosteal wrap. De novo bone growth was evaluated using histological and radiological analysis. Of importance, the experimental model was well tolerated by the animals and provides a versatile approach for comparing the osteogenic potential of cambium on the bone surface and elevated with periosteum. Furthermore, the periosteal flaps were sufficiently large for encasing bioreactors containing biomaterial bone substitutes for applications such as segmental mandibular reconstruction.

Autologous bone replacement remains the preferred treatment for segmental defects of the mandible; however, it cannot replicate complex facial geometry and causes donor site morbidity. Bone tissue engineering has the potential to overcome these limitations. Various commercially available calcium phosphate-based bone substitutes (Novabone^®, BioOss^®, and Zengro^®) are commonly used in dentistry for small bone defects around teeth and implants. However, their role in ectopic bone formation, which can later be applied as vascularized graft in a bone defect, is yet to be explored. Here, we compare the above-mentioned bone substitutes with autologous bone with the aim of selecting one for future studies of segmental mandibular repair. Six female sheep, aged 7–8 years, were implanted with 40 mm long four-chambered polyether ether ketone (PEEK) bioreactors prepared using additive manufacturing followed by plasma immersion ion implantation (PIII) to improve hydrophilicity and bioactivity. Each bioreactor was wrapped with vascularized scapular periosteum and the chambers were filled with autologous bone graft, Novabone^®, BioOss^®, and Zengro^®, respectively. The bioreactors were implanted within a subscapular muscle pocket for either 8 weeks (two sheep), 10 weeks (two sheep), or 12 weeks (two sheep), after which they were removed and assessed by microCT and routine histology. Moderate bone formation was observed in autologous bone grafts, while low bone formation was observed in the BioOss^® and Zengro^® chambers. No bone formation was observed in the Novabone^® chambers. Although the BioOss^® and Zengro^® chambers contained relatively small amounts of bone, endochondral ossification and retained hydroxyapatite suggest their potential in new bone formation in an ectopic site if a consistent supply of progenitor cells and/or growth factors can be ensured over a longer duration.

The periosteum is a thin layer of connective tissue covering bone. It is an essential component for bone development and fracture healing. There has been considerable research exploring the application of the periosteum in bone regeneration since the 19th century. An increasing number of studies are focusing on periosteal progenitor cells found within the periosteum and the use of hydrogels as scaffold materials for periosteum engineering and guided bone development. Here, we provide an overview of the research investigating the use of the periosteum for bone repair, with consideration given to the anatomy and function of the periosteum, the importance of the cambium layer, the culture of periosteal progenitor cells, periosteum-induced ossification, periosteal perfusion, periosteum engineering, scaffold vascularization, and hydrogel-based synthetic periostea.

Viruses are well known drivers of several human malignancies. A causative factor for oral cavity squamous cell carcinoma (OSCC) in patients with limited exposure to traditional risk factors, including tobacco use, is yet to be identified. Our study aimed to comprehensively evaluate the role of viral drivers in OSCC patients with low cumulative exposure to traditional risk factors. Patients under 50 years of age with OSCC, defined using strict anatomic criteria were selected for WGS. The WGS data was interrogated using viral detection tools (Kraken 2 and BLASTN), together examining >700,000 viruses. The findings were further verified using tissue microarrays of OSCC samples using both immunohistochemistry and RNA in situ hybridisation (ISH). 28 patients underwent WGS and comprehensive viral profiling. One 49-year-old male patient with OSCC of the hard palate demonstrated HPV35 integration. 657 cases of OSCC were then evaluated for the presence of HPV integration through immunohistochemistry for p16 and HPV RNA ISH. HPV integration was seen in 8 (1.2%) patients, all middle-aged men with predominant floor of mouth involvement. In summary, a wide-ranging interrogation of >700,000 viruses using OSCC WGS data showed HPV integration in a minority of male OSCC patients and did not carry any prognostic significance.

Long-term health-related quality of life (HRQOL) and functional outcomes following mandibular and maxillary reconstruction are lacking. To determine these outcomes, a cross-sectional study of patients with a history of cancer who underwent jaw reconstruction was undertaken. Participants were identified from a database of jaw reconstruction procedures at the Chris O’Brien Lifehouse (Sydney, Australia). Eligible patients had at least one month follow-up, were aged ≥18 years at surgery, and had history of malignancy. HRQOL was measured using the FACE-Q Head and Neck Cancer Module (FACE-Q H&N). Functional outcomes were measured using the FACE-Q H&N, MD Anderson Dysphagia Inventory (MDADI) and Speech Handicap Index (SHI). Ninety-seven questionnaires were completed (62% response rate). Mean age of respondents was 63.7 years, 61% were male, and 64% underwent radiotherapy. Treatment with radiotherapy was associated with worse outcomes across 10/14 FACE-Q H&N scales, three MDADI subscales and one composite score, and the SHI. Mean differences in scores between irradiated and non-irradiated patients exceeded clinically meaningful differences for the MDADI and SHI. Issues with oral competence, saliva, speaking, and swallowing worsened with increasing time since surgery. Younger patients reported greater concerns with appearance, smiling, speaking, and cancer worry. Women reported greater concerns regarding appearance and associated distress. History of radiotherapy substantially impacts HRQOL and function after jaw reconstruction. Age at surgery and gender were also predictors of outcomes and associated distress. Pre-treatment counselling of patients requiring jaw reconstruction may lead to improved survivorship for patients with head and neck cancer.

Background: Microvascular free‐flap reconstruction of the head and neck is a common technique utilized across many ages. The purpose of this study was to identify if advanced age or comorbidity was associated with worse post‐operative outcomes in patients undergoing free‐flap reconstruction.Methods: A retrospective analysis was performed on 344 consecutive patients undergoing free‐flap surgery of the head and neck. Demographic, clinical and pathological factors were considered along with Charlson Comorbidity Index (CCI) scores and American Society of Anesthesiologists (ASA) status. Logistic regression analysis was used to investigate the association of age, CCI or ASA with post‐operative complications.Results: Elderly patients (≥75 years) had a higher overall complication rate (odds ratio (OR) 1.7, P = 0.04) that was restricted to medical complications (OR 2.1, P = 0.05) and not surgical complications (OR 1.4, P = 0.14). Reconstructions of defects from cutaneous malignancy predominated in the elderly cohort (48% versus 29%, P < 0.01), but there was no difference in complication rate when cutaneous or mucosal subgroups were separated by age. ASA IV status was weakly associated with surgical complications (OR 3.89, P = 0.053), but CCI and elderly age were not associated with any outcome. Median length of stay was similar between age groups.Conclusion: Free‐flap reconstruction in older patients was associated with increased medical complications, and surgical complications were weakly associated with ASA status. Advanced age or comorbidity should not preclude microvascular reconstruction, but comorbid status should be optimized pre‐operatively and factors predisposing to medical complications minimized where possible.