Biomechanical evaluation of CAD/CAM magnesium miniplates as a fixation strategy for the treatment of segmental mandibular reconstruction with a fibula free flap.

Titanium patient-specific (CAD/CAM) plates are frequently used in mandibular reconstruction. However, titanium is a very stiff, non-degradable material which also induces artifacts in the imaging. Although magnesium has been proposed as a potential material alternative, the biomechanical conditions in the reconstructed mandible under magnesium CAD/CAM plate fixation are unknown. This study aimed to evaluate the primary fixation stability and potential of magnesium CAD/CAM miniplates. The biomechanical environment in a one segmental mandibular reconstruction with fibula free flap induced by a combination of a short posterior titanium CAD/CAM reconstruction plate and two anterior CAD/CAM miniplates of titanium and/or magnesium was evaluated, using computer modeling approaches. Output parameters were the strains in the healing regions and the stresses in the plates. Mechanical strains increased locally under magnesium fixation. Two plate-protective constellations for magnesium plates were identified: (1) pairing one magnesium miniplate with a parallel titanium miniplate and (2) pairing anterior magnesium miniplates with a posterior titanium reconstruction plate. Due to their degradability and reduced stiffness in comparison to titanium, magnesium plates could be beneficial for bone healing. Magnesium miniplates can be paired with titanium plates to ensure a non-occurrence of plate failure.

Quantifying bone healing after mandibular displacement in orthognathic surgery.

Impaired bony healing following bilateral sagittal split osteotomy (BSSO) is a major unmet medical need for affected patients, and rare occurrences can hinder the identification of underlying risk factors. We hypothesised that osseous union following BSSO can be quantified using volumetric analysis, and we aimed to identify the risk factors for impaired bone healing. The percentage change in bony volume was measured in orthognathic patients following BSSO using two consecutive postoperative cone-beam computed tomography scans. Patients' characteristics and treatment parameters were documented, and correlation and regression analyses of these variables performed. Thirty-six patients (23 men and 13 women) with a mean (SD) age of 33.28 (11.86) years were included. The gap site (lingual versus buccal) (p < 0.01) had a significant impact on the change in volume. Age (p = 0.06) showed a trend towards significance. Initial width of the osteotomy gap, sex, and indication for surgery did not influence osseous healing. Increased age at surgery and the side of the buccal osteotomy are independent risk factors for impaired osseous healing following BSSO.

Impact of the adjacent bone on pseudarthrosis in mandibular reconstruction with fibula free flaps.

BACKGROUND: Mechanical and morphological factors have both been described to influence the rate of pseudarthrosis in mandibular reconstruction. By minimizing mechanical confounders, the present study aims to evaluate the impact of bone origin at the intersegmental gap on osseous union. METHODS: Patients were screened retrospectively for undergoing multi-segment fibula free flap reconstruction of the mandible including the anterior part of the mandible and osteosynthesis using patient-specific 3D-printed titanium reconstruction plates. Percentage changes in bone volume and width at the bone interface between the fibula/fibula and fibula/mandible at the anterior intersegmental gaps within the same patient were determined using cone-beam computed tomography (CBCT). Additionally, representative samples of the intersegmental zones were assessed histologically and using micro-computed tomography (µCT). RESULTS: The bone interface (p = 0.223) did not significantly impact the change in bone volume at the intersegmental gap. Radiotherapy (p < 0.001), time between CBCT scans (p = 0.006) and wound healing disorders (p = 0.005) were independent risk factors for osseous non-union. Preliminary analysis of the microstructure of the intersegmental bone did not indicate morphological differences between fibula-fibula and fibula-mandible intersegmental bones. CONCLUSIONS: The bone interface at the intersegmental gap in mandibular reconstruction did not influence long-term bone healing significantly. Mechanical and clinical properties seem to be more relevant for surgical success.

The Use of Regional Anesthesia to Reduce Blood Loss in Isolated Limb Perfusion (ILP)-A Novel Approach.

BACKGROUND: Isolated limb perfusion (ILP) for soft tissue sarcomas (STS) is usually performed with tumor necrosis factor alpha (TNF-α) and melphalan. ILP regularly leads to a total blood loss (BLt) of 1.5-2 L/patient. Blood inflow from the central blood circulation to the limb is influenced by unstable pressure gradients and pain reactions after the administration of melphalan. With perioperative regional anesthesia (RA), pain levels can be reduced, and the pressure gradient stabilized resulting in a reduced BLt. The aim of this study was to compare the BLt with and without RA in patients with ILP during circulation of drugs. METHODS: Patients were treated according to the following protocol: After the establishment of limb circulation, ILP was started with the administration of TNF-α. Half the dose of melphalan was given as a bolus after 30 min, and the remaining dose was continuously administered in the following 30 min. The extremity was washed out after 90 min. ILP with perioperative RA (supraclavicular plexus block/peridural catheter) was performed prospectively in 17 patients and compared to a matched retrospective control group of 17 patients without RA. BLt was documented and perioperative anesthesiological data were analyzed for response rates after the application of melphalan (RaM). RESULTS: BLt and RaM tended to be lower for the intervention group with RA if compared to the control group without RA in all analyses. The trend of lower BLt and RaM in ILP with RA was more pronounced for the upper extremity compared to the lower extremity. Results were not statistically significant. CONCLUSION: These findings indicate that the use of RA can help to stabilize hemodynamic anesthetic management and reduce the BLt in ILP, especially during perfusion of the upper extremities.

Patients ' perspectives on bone replacement materials in a German university hospital setting.

BACKGROUND: The challenges in developing new bone replacement materials and procedures reside not solely in technological innovation and advancement, but also in a broader patient therapy acceptance. Therefore, there is a need to assess patients' perspectives on the materials and approaches in use as well as the ones being developed to better steer future progress in the field. METHODS: A self-initiating cross-sectional questionnaire aimed at people seeking treatment at the university hospital environment of Charité Berlin was formulated. The survey contained 15 close-ended questions directed toward the participant's epidemiological profile, willingness, acceptance, and agreement to receive different bone replacement materials, as well as, worries about the post-surgical consequences that can arise post bone replacement surgery. Descriptive and categorical analysis was performed to compare the observed number of subjects, their profile and each related response (Pearson's chi-square test or Fischer's test, p < 0.05). RESULTS: A total of 198 people engaged with the questionnaire, most of them Millennials. Overall patients trusted scientifically developed biomaterials designed for bone replacement, as demonstrated by their willingness to participate in a clinical trial, their acceptance of alloplastic materials, and the none/few worries about the presence of permanent implants. The data revealed the preferences of patients towards autologous sources of cells and blood to be used with a biomaterial. The data have also shown that both generation and education influenced willingness to participate in a clinical trial and acceptance of alloplastic materials, as well as, worries about the presence of permanent implants and agreement to receive a material with pooled blood and cells. CONCLUSION: Patients were open to the implantation of biomaterials for bone replacement, with a preference toward autologous sources of blood and/or tissue. Moreover, patients are concerned about strategies based on permanent implants, which indicates a need for resorbable materials. The knowledge gained in this study supports the development of new bone biomaterials.

Treatment options for critical size defects - Comparison of different materials in a calvaria split model in sheep.

Bone defects of the craniofacial skeleton are often associated with aesthetic and functional impairment as well as loss of protection to intra- and extracranial structures. Solid titanium plates and individually adapted bone cements have been the materials of choice, but may lead to foreign-body reactions and insufficient osseointegration. In contrast, porous scaffolds are thought to exhibit osteoconductive properties to support bone ingrowth. Here, we analyse in critical size defects of the calvaria in sheep whether different bone replacement materials may overcome those remaining challenges. In a critical size defect model, bilateral 20 × 20 × 5-mm craniectomies were performed on either side of the sagittal sinus in 24 adult female blackheaded sheep. Bony defects were randomised to one of five different bone replacement materials (BRMs): titanium scaffold, biodegradable poly(d,l-lactic acid) calcium carbonate scaffold (PDLLA/CC), polyethylene 1 (0.71 mm mean pore size) or 2 (0.515 mm mean pore size) scaffolds and polymethyl methacrylate (PMMA)-based bone cement block. Empty controls (n = 3) served as references. To evaluate bone growth over time, three different fluorochromes were administered at different time points. At 3, 6 and 12 months after surgery, animals were sacrificed and the BRMs and surrounding bone analysed by micro-CT and histomorphometry. The empty control group verified that the calvaria defect in this study was a reliable critical size defect model. Bone formation in vivo was detectable in all BRMs after 12 months by micro-CT and histomorphometric analysis, except for the non-porous PMMA group. A maximum of bone formation was detected in the 12-months group for titanium and PDLLA/CC. Bone formation in PDLLA/CC starts to increase rapidly between 6 and 12 months, as the BRM resorbs over time. Contact between bone and BRM influenced bone formation inside the BRM. Empty controls exhibited bone formation solely at the periphery. Overall, porous BRMs offered bone integration to different extent over 12 months in the tested calvaria defect model. Titanium and PDLLA/CC scaffolds showed remarkable osseointegration properties by micro-CT and histomorphometric analysis. PDLLA/CC scaffolds degraded over time without major residues. Pore size influenced bone ingrowth in polyethylene, emphasising the importance of porous scaffold structure.

Increased rate of pseudarthrosis in the anterior intersegmental gap after mandibular reconstruction with fibula free flaps: a volumetric analysis.

OBJECTIVES: Pseudarthrosis after mandibular reconstruction leads to chronic overload of the osteosynthesis and impedes dental rehabilitation. This study evaluates the impact of gap site on osseous union in mandible reconstruction using a new volumetric analysis method with repeated cone-beam computed tomography (CBCT). METHODS: The degree of bone regeneration was evaluated in 16 patients after mandible reconstruction with a fibula free flap and patient-specific reconstruction plates. Percentual bone volume and width changes in intersegmental gaps were retrospectively analyzed using a baseline CBCT in comparison to a follow-up CBCT. Patients' characteristics, plate-related complications, and gap sites (anterior/posterior) were analyzed. Detailed assessments of both gap sites (buccal/lingual/superior/inferior) were additionally performed. RESULTS: Intersegmental gap width (p = 0.002) and site (p < 0.001) significantly influence bone volume change over two consecutive CBCTs. An initial larger gap width resulted in a lower bone volume change. In addition, anterior gaps showed significantly less bone volume changes. Initial gap width was larger at posterior segmental gaps (2.97 vs 1.65 mm, p = 0.017). CONCLUSIONS: A methodology framework has been developed that allows to quantify pseuarthrosis in reconstructed mandibles using CBCT imaging. The study identifies the anterior segmental gap as a further risk factor for pseudarthrosis in reconstructions with CAD/CAM reconstruction plates. Future research should evaluate whether this outcome is related to the biomechanics induced at this site.

Histological Processing of CAD/CAM Titanium Scaffold after Long-Term Failure in Cranioplasty.

Cranioplasty is a frequently performed procedure after craniectomy and includes several techniques with different materials. Due to high overall complication rates, alloplastic implants are removed in many cases. Lack of implant material osseointegration is often assumed as a reason for failure, but no study has proven this in cranioplasty. This study histologically evaluates the osteointegration of a computer-aided design and computer-aided manufacturing (CAD/CAM) titanium scaffold with an open mesh structure used for cranioplasty. A CAD/CAM titanium scaffold was removed due to late soft tissue complications 7.6 years after cranioplasty. The histological analyses involved the preparation of non-decalcified slices from the scaffold's inner and outer sides as well as a light-microscopic evaluation, including the quantification of the bone that had formed over the years. Within the scaffold pores, vital connective tissue with both blood vessels and nerves was found. Exclusive bone formation only occurred at the edges of the implant, covering 0.21% of the skin-facing outer surface area. The inner scaffold surface, facing towards the brain, did not show any mineralization at all. Although conventional alloplastic materials for cranioplasty reduce surgery time and provide good esthetic results while mechanically protecting the underlying structures, a lack of adequate stimuli could explain the limited bone formation found. CAD/CAM porous titanium scaffolds alone insufficiently osseointegrate in such large bone defects of the skull. Future research should investigate alternative routes that enable long-term osteointegration in order to reduce complication rates after cranioplasty. Opportunities could be found in mechano-biologically optimized scaffolds, material modifications, surface coatings, or other routes to sustain bone formation.

Improved in vivo osseointegration and degradation behavior of PEO surface-modified WE43 magnesium plates and screws after 6 and 12 months.

Magnesium is a highly promising candidate with respect to its future use as a material for resorbable implants. When magnesium degrades, hydrogen gas is released. High doses of gas emergence are reported to impair osseointegration and may therefore lead to fixation failure. The successful delay and reduction of the degradation rate by applying plasma electrolytic oxidation (PEO) as a post processing surface modification method for magnesium alloy has recently been demonstrated. The aim of this study was thus to compare the degradation behavior of a WE43-based plate system with and without respective PEO surface modification and to further investigate osseointegration, as well as the resulting effects on the surrounding bony tissue of both variants in a miniature pig model. WE43 magnesium screws and plates without (WE43) and with PEO surface modification (WE43-PEO) were implanted in long bones of Göttingen Miniature Pigs. At six and twelve months after surgery, micro-CT and histomorphometric analysis was performed. Residual screw volume (SV/TV; WE43: 28.8 ± 21.1%; WE43-PEO: 62.9 ± 31.0%; p = 0.027) and bone implant contact area (BIC; WE43: 18.1 ± 21.7%; WE43-PEO: 51.6 ± 27.7%; p = 0.015) were increased after six months among the PEO-modified implants. Also, surrounding bone density within the cortical bone was not affected by surface modification (BVTV; WE43: 76.7 ± 13.1%; WE43-PEO: 73.1 ± 16.2%; p = 0.732). Intramedullar (BV/TV; WE43: 33.2 ± 16.7%; WE43-PEO 18.4 ± 9.0%; p = 0.047) and subperiosteal (bone area; WE43: 2.6 ± 3.4 mm2; WE43-PEO: 6,9 ± 5.2 mm2; p = 0.049) new bone formation was found for both, surface-modified and non-surface-modified groups. After twelve months, no significant differences of SV/TV and BV/TV were found between the two groups. PEO surface modification of WE43 plate systems improved osseointegration and significantly reduced the degradation rate within the first six months in vivo. Osteoconductive and osteogenic stimulation by WE43 magnesium implants led to overall increased bone growth, when prior PEO surface modification was conducted.

The multifaceted roles of macrophages in bone regeneration: A story of polarization, activation and time.

To present knowledge, macrophages are found in all tissues of the human body. They are a cell population with high plasticity which come with a multitude of functions which appear to be adapted to the respective tissue niche and micro-environment in which they reside. Bone harbors multiple macrophage subpopulations, with the osteoclasts as classical representative of a bone resorbing cells and osteomacs as a bone tissue resident macrophage first described by the expression of F4/80. Both subtypes are found throughout all phases in bone healing. In vivo data on bone regeneration have demonstrated their essential role in initiating the healing cascade (inflammatory phase) but also of the later phases of healing (e.g. endochondral and intramembranous bone formation). To participate in such diverse processes macrophages have to be highly plastic in their functionality. Thus, the widely used M1/M2 paradigm to distinguish macrophage subpopulations may not mirror the comprehensive role of the dynamics of macrophage plasticity. From a clinical perspective it is especially relevant to distinguish what drives macrophages in impaired healing scenarios, implant loosening or infections, where their specific role of a misbalanced inflammatory setting is so far only partially known. With this review we aim at illustrating current knowledge and gaps of knowledge on macrophage plasticity and function during the cascades of regeneration and reconstitution of bone tissue. We propose aspects of the known biological mechanisms of macrophages and their specific subsets that might serve as targets to control their function in impaired healing and eventually support a scar-free regeneration. STATEMENT OF SIGNIFICANCE: Macrophages are essential for successful regeneration. In scar-free healing such as in bone, a complete failure of healing was shown if macrophages were depleted; the M1/M2 switch appears to be key to the progression from pro-inflammation to regeneration. However, experimental data illustrate that the classical M1/M2 paradigm does not completely mirror the complexity of observed macrophage functions during bone healing and thus demands a broader perspective. Within this review we discuss the high degree of plasticity of macrophages and the relevant contribution of the different and more specific M2 subtypes (M2a-M2f) during (bone) regeneration. It summarizes the versatile roles of macrophages in skeletal regeneration and thereby highlights potential target points for immunomodulatory approaches to enable or even foster bone repair.