Additive Manufacturing (AM) allows the creation of personalized medical models, tools, and implants. Patient-specific structures can be fabricated faithfully, quickly and reliably. The production of orthopedic implants by means of AM could greatly benefit from multi-material structures. The skeletal system is composed of hard bones and softer cartilage, performing different tasks in the body. Multi-material implant structures require biocompatible materials that can withstand in-body conditions for extended periods of time. Among possible material candidates, polyurethanes have been selected for further investigation. This project studied two medical-grade polyurethanes (with established clinical history for long-term implants) produced by DSM Biomedical with a Shore hardness of 75D and 80A. They were used to fabricate three-dimensional structures with the thermoplastic material jetting technique (MJT) known as Arburg Plastic Freeforming (APF). Tensile and bending specimens were produced for the individual polyurethanes by applying optimized processing parameters. Also, multi-material specimens were manufactured to analyze fracture failure at the interface between the two polyurethanes in tension. Based on information collected in this investigation, recommendations on preparing implantable structures such as rib replacement systems, are given.

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Postnatal bone growth primarily relies on chondrocyte proliferation and osteogenic differentiation within the growth plate (GP) via endochondral ossification. Despite its importance, the GP is vulnerable to injuries, affecting 15-30 % of bone fractures. These injuries may lead to growth discrepancies, influence bone length and shape, and negatively affecting the patient's quality of life. This study aimed to investigate the molecular and cellular physiological and pathophysiological regeneration following sustained growth plate injury (GPI) in an ex vivo rat femur organotypic culture (OTC) model. Specifically, focusing on postnatal endochondral ossification process. 300 μm thick ex vivo bone cultures with a 2 mm long horizontal GPI was utilized. After 15 days of cultivation, gene expression analysis, histological and immunohistochemistry staining's were conducted to analyze key markers of endochondral ossification. In our OTCs we observed a significant increase in Sox9 expression due to GPI at day 15. The Ihh-PTHrP feedback loop was affected, favoring chondrocyte proliferation and maturation. Ihh levels increased significantly on day 7 and day 15, while PTHrP was downregulated on day 7. GPI had no impact on osteoclast number and activity, but gene expression analysis indicated OTCs' efforts to inhibit osteoclast differentiation and activation, thereby reducing bone resorption. In conclusion, our study provides novel insights into the molecular and cellular mechanisms underlying postnatal bone growth and regeneration following growth plate injury (GPI). We demonstrate that chondrocyte proliferation and differentiation play pivotal roles in the regeneration process, with the Ihh-PTHrP feedback loop modulating these processes. Importantly, our ex vivo rat femur organotypic culture model allows for the detailed investigation of these processes, providing a valuable tool for future research in the field of skeletal biology and regenerative medicine.

Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat tumors such as the most lethal brain tumors, glioblastomas (GBM). However, despite high toxicity for GBM cells, potent chemotherapeutics such as gemcitabine (Gem) cannot be widely implemented as they do not efficiently cross the blood brain barrier (BBB). As an alternative method for continuous administration of Gem, we here operate freestanding iontronic pumps - "GemIPs" - equipped with a custom-synthesized ion exchange membrane (IEM) to treat a GBM tumor in an avian embryonic in vivo system. We compare GemIP treatment effects with a topical metronomic treatment and observe that a remarkable growth inhibition was only achieved with steady dosing via GemIPs. Daily topical drug administration (at the maximum dosage that was not lethal for the embryonic host organism) did not decrease tumor sizes, while both treatment regimes caused S-phase cell cycle arrest and apoptosis. We hypothesize that the pharmacodynamic effects generate different intratumoral drug concentration profiles for each technique, which causes this difference in outcome. We created a digital model of the experiment, which proposes a fast decay in the local drug concentration for the topical daily treatment, but a long-lasting high local concentration of Gem close to the tumor area with GemIPs. Continuous chemotherapy with iontronic devices opens new possibilities in cancer treatment: the long-lasting and highly local dosing of clinically available, potent chemotherapeutics to greatly enhance treatment efficiency without systemic side-effects. Significance statement: Iontronic pumps (GemIPs) provide continuous and localized administration of the chemotherapeutic gemcitabine (Gem) for treating glioblastoma in vivo. By generating high and constant drug concentrations near the vascularized growing tumor, GemIPs offer an efficient and less harmful alternative to systemic administration. Continuous GemIP dosing resulted in remarkable growth inhibition, superior to daily topical Gem application at higher doses. Our digital modelling shows the advantages of iontronic chemotherapy in overcoming limitations of burst release and transient concentration profiles, and providing precise control over dosing profiles and local distribution. This technology holds promise for future implants, could revolutionize treatment strategies, and offers a new platform for studying the influence of timing and dosing dependencies of already -established drugs in the fight against hard -to -treat tumors.

Additive manufacturing (AM) nowadays has become a supportive method of traditional manufacturing. In particular, the medical and healthcare industry can profit from these developments in terms of personalized design and batches ranging from one to five specimens overall. In terms of polymers, polyolefins are always an interesting topic due to their low prices, inert chemistry, and crystalline structure resulting in preferable mechanical properties. Their semi-crystalline nature has some advantages but are challenging for AM due to their shrinkage and warping, resulting in geometrical inaccuracies or even layer detaching during the process. To tackle these issues, process parameter optimization is vital, with one important parameter to be studied more in detail, the print envelope temperature. It is well known that higher print envelope temperatures lead to better layer adhesion overall, but this investigation focuses on the mechanical properties and resulting morphology of a semi-crystalline thermoplastic polyolefin. Further, two different AM technologies, namely material jetting (ARBURG plastic freeforming—APF) and filament-based material extrusion, were studied and compared in detail. It was shown that higher print envelope temperatures lead to more isotropic behavior based on an evenly distributed morphology but results in geometrical inaccuracies since the material is kept in a molten state during printing. This phenomenon especially could be seen in the stress and strain values at break at high elongations. Furthermore, a different crystal structure can be achieved by setting a specific temperature and printing time, also resulting in peak values of certain mechanical properties. In comparison, better results could be archived by the APF technology in terms of mechanical properties and homogeneous morphology. Nevertheless, real isotropic part behavior could not be managed which was shown by the specimen printed vertically. Hence, a sweet spot between geometrical and mechanical properties still has to be found.

Additive manufacturing finds more applications every day, especially in medical devices, ranging from models, tools, to implants. The fabricated parts have to withstand the mechanical loading applied during their lifetime. Hence, optimization of process parameters must be performed to reach the best performance of the manufactured part with the given polymer. A fractional design of experiments is performed with the ARBURG plastic freeforming using a medical‐grade poly (methyl methacrylate) to improve the overall mechanical performance. Tensile specimens are produced, tested, and the impact of different parameter settings is analyzed to identify the factors with the highest impact on the mechanical performance. Based on the results, further parameter optimization is performed. A direct correlation between the density and the tensile properties of the printed parts is observed. Further, an influence of the processing pressure resulting from changes in the processing temperature is detected. Optimization for good mechanical performance is performed, and a relation between the filling of the parts, the nozzle temperature, and the discharge pressure on to the tensile properties is found. This investigation reveals that shrinkage due to changes in temperature and pressure has an essential role in determining the tensile properties of specimens produced by ARBURG plastic freeforming.

Postnatal bone fractures of the growth plate (GP) are often associated with regenerative complications such as growth impairment. In order to understand the underlying processes of trauma-associated growth impairment within postnatal bone, an ex vivo rat femur slice model was developed. To achieve this, a 2 mm horizontal cut was made through the GP of rat femur prior to the organotypic culture being cultivated for 15 days in vitro. Histological analysis showed disrupted endochondral ossification, including disordered architecture, increased chondrocyte metabolic activity, and a loss of hypertrophic zone throughout the distal femur. Furthermore, altered expression patterns of Col2α1, Acan, and ColX, and increased chondrocyte metabolic activity in the TZ and MZ at day 7 and day 15 postinjury were observed. STEM revealed the presence of stem cells, fibroblasts, and chondrocytes within the injury site at day 7. In summary, the findings of this study suggest that the ex vivo organotypic GP injury model could be a valuable tool for investigating the underlying mechanisms of GP regeneration post-trauma, as well as other tissue engineering and disease studies.

Particle therapy (PT) that utilizes protons and carbon ions offers a promising way to reduce the side effects of radiation oncology, especially in pediatric patients. To investigate the influence of PT on growing bone, we exposed an organotypic rat ex vivo femur culture model to PT. After irradiation, histological staining, immunohistochemical staining, and gene expression analysis were conducted following 1 or 14 days of in vitro culture (DIV). Our data indicated a significant loss of proliferating chondrocytes at 1 DIV, which was followed by regeneration attempts through chondrocytic cluster formation at 14 DIV. Accelerated levels of mineralization were observed, which correlated with increased proteoglycan production and secretion into the pericellular matrix. Col2α1 expression, which increased during the cultivation period, was significantly inhibited by PT. Additionally, the decrease in ColX expression over time was more pronounced compared to the non-IR control. The chondrogenic markers BMP2, RUNX2, OPG, and the osteogenic marker ALPL, showed a significant reduction in the increase in expression after 14 DIV due to PT treatment. It was noted that carbon ions had a stronger influence than protons. Our bone model demonstrated the occurrence of pathological and regenerative processes induced by PT, thus building on the current understanding of the biological mechanisms of bone.

Nowadays, personalized medical implants are frequently produced through additive manufacturing. As all medical devices have to undergo specific washing and sterilization before application, the effects of a predefined cleaning routine that is available to the clinical institutes, washing with chemical agent and formaldehyde fumigation, on the mechanical behavior of printed parts are examined. Mechanical properties of parts manufactured by fused filament fabrication (FFF) and ARBURG plastic freeforming (APF) using two poly(methyl methacrylate) (PMMA)‐based materials, 3Diakon and CYROLITE MD H12, respectively, are analyzed using flexural and impact tests. An influence of cleaning treatments on the mechanical properties of APF samples is not detected. FFF samples, however, show lower impact strength after washing, but not after sterilization. The fracture surfaces, porosity values, or chemical structure assessed by Fourier‐transform infrared (FTIR) spectroscopy could not explain this decrease. Influence of the cleaning treatments on the material itself is assessed using thin compression‐molded specimens. The influence on the stress–strain curves is negligible, apart from a slight but significant reduction in the yield stress. FTIR spectroscopy and scanning electron microscopy analyses of the fracture surfaces do not show detectable differences among differentially treated samples.

Polyetheretherketone (PEEK) is a high performing thermoplastic that has established itself as a 'gold-standard' material for cranial reconstruction. Traditionally, milled PEEK patient specific cranial implants (PSCIs) exhibit uniform levels of smoothness (excusing suture/drainage holes) to the touch (<1 μm) and homogenous coloration throughout. They also demonstrate predictable and repeatable levels of mechanical performance, as they are machined from isotropic material blocks. The combination of such factors inspires confidence from the surgeon and in turn, approval for implantation. However, manufacturing lead-times and affiliated costs to fabricate a PSCI are high. To simplify their production and reduce expenditure, hospitals are exploring the production of in-house PEEK PSCIs by material extrusion-based additive manufacturing. From a geometrical and morphological perspective, such implants have been produced with good-to-satisfactory clinical results. However, lack of clinical adoption persists. To determine the reasoning behind this, it was necessary to assess the benefits and limitations of current printed PEEK PSCIs in order to establish the status quo. Afterwards, a review on individual PEEK printing variables was performed in order to identify a combination of parameters that could enhance the aesthetics and performance of the PSCIs to that of milled implants/cranial bone. The findings from this review could be used as a baseline to help standardize the production of PEEK PSCIs by material extrusion in the hospital.

Polyetheretherketone (PEEK) is considered a ‘gold-standard’ material choice for cranial bone reconstruction. The introduction of additive manufacturing (AM) into the pipeline for patient specific cranial implant (PSCI) fabrication could accelerate supply chain needs and improve patient outcomes. Fused filament fabrication (FFF), a material extrusion-based technology, is a much-researched process due to its accessibility and ease of use. However, the quality of PEEK processed by FFF is highly affected by the applied printing profile. Therefore, in this study, the effects of printing parameters such as build orientation and air flow temperature on mechanical performance (cyclic and impact tests) and implant quality (characterisation of surface topography, discoloration and crystallinity) were analysed and compared with a commercial milled PEEK implant. It has been found that horizontally printed implants show higher mechanical integrity compared to implants printed upright or tilted by 45°, but obtain lower surface quality. In addition, lower air flow temperatures lead to strong implant discolorations due to high amounts of amorphousness, which further result in high absorbed energies during impact as well as large deformations until complete failure. The best results from a mechanical point of view were achieved with PSCIs printed at a build orientation of 180°, an air flow temperature of 210 °C, a shell number of 3, a layer height of 0.15 mm, a printing speed of 50 mm/min, a rectilinear ±45° infill pattern and an implant thickness of 5 mm. However, the surface quality of implants produced this way is not completely satisfactory, and the arrangement of the support structures must be further improved.

To treat bone fractures, implant manufacturers produce 2D anatomically contoured plates. Unfortunately, existing plates only fit a limited segment of the population and/or require manual bending during surgery. Patient-specific implants would provide major benefits such as reducing surgery time and improving treatment outcomes but they are still rare in clinical practice. In this work, we propose a patient-specific design for the long helical 2D PHILOS (Proximal Humeral Internal Locking System) plate, used to treat humerus shaft fractures. Our method automatically creates a custom plate from a CT scan of a patient's bone. We start by designing an optimal plate on a template bone and, with an anatomy-aware registration method, we transfer this optimal design to any bone. In addition, for an arbitrary bone, our method assesses if a given plate is fit for surgery by automatically positioning it on the bone. We use this process to generate a compact set of plate shapes capable of fitting the bones within a given population. This plate set can be pre-printed in advance and readily available, removing the fabrication time between the fracture occurrence and the surgery. Extensive experiments on ex-vivo arms and 3D-printed bones show that the generated plate shapes (personalized and plate-set) faithfully match the individual bone anatomy and are suitable for clinical practice.

Surgical resection of chest wall tumours may lead to a loss of ribcage stability and requires reconstruction to allow for physical thorax functioning. When titanium implants are used especially for larger, lateral defects, they tend to break. Implant failures are mainly due to specific mechanical requirements for chest-wall reconstruction which must mimic the physiological properties and which are not yet met by available implants. In order to develop new implants, the mechanical characteristics of ribs, joints and cartilages are investigated. Rib loading is highly dependent on the global thorax kinematics, making implant development substantially challenging. Costal cartilage contributes vastly to the entire thorax load-deformation behaviour, and also to rib loading patterns. Computational models of the thoracic cage require mechanical properties on the global stiffness, to simulate rib kinematics and evaluate stresses in the ribs and costal cartilage. In this study the mechanical stiffness of human costal cartilage is assessed with bending, torsion and tensile tests. The elastic moduli for the bending in four major directions ranged from 2.2 to 60.8 MPa, shear moduli ranged from 5.7 to 24.7 MPa for torsion, and tensile elastic moduli ranging from 5.6 to 29.6 MPa. This article provides mechanical properties for costal cartilage. The results of these measurements are used for the development of a whole thorax finite element model to investigate ribcage biomechanics and subsequently to design improved rib implants.

The combination of computer – aided design (CAD) techniques based on computed tomography (CT) data support the planning of patient – specific implants massively. During the last decade, Geometric Morphometric (GMM) methods utilizing thin – plate splines (TPS) were increasingly used to estimate missing data in clinical cases that are characterized by large skull defects featuring partly and completely missing midsagittal planes. Applying a dedicated reconstruction protocol, GMM methods enable the design of personalized cranial implants that accurately reproduce the bone thickness of the affected area. In this study we applied a TPS based reconstruction approach to design a cranial implant of a clinical case that features the bone thickness distribution in the affected region. This virtual model was subsequently additively manufactured (AM) by fused filament fabrication (FFF) using polyetheretherketone (PEEK). The 3D - printed implant was non – destructively investigated via X-ray microcomputed tomography (XCT). The nominal – actual comparison between the designed virtual model and XCT scan of the final implant showed an average deviation in terms of root mean square (RMS) error of 0.168 mm. Additionally, a pore analysis of the 3D printed implant was carried out showing a porosity of 0.07%.

Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS) and progressively leads to physical disability and death, caused by white matter lesions in the spinal cord and cerebellum, as well as by demyelination in grey matter. Whilst conventional models of experimental allergic encephalomyelitis are suitable for the investigation of the cell-mediated inflammation in the spinal and cerebellar white matter, they fail to address grey matter pathologies. Here, we present the experimental protocol for a novel rat model of cortical demyelination allowing the investigation of the pathological and molecular mechanisms leading to cortical lesions. The demyelination is induced by an immunization with low-dose myelin oligodendrocyte glycoprotein (MOG) in an incomplete Freund's adjuvant followed by a catheter-mediated intracerebral delivery of pro-inflammatory cytokines. The catheter, moreover, enables multiple rounds of demyelination without causing injection-induced trauma, as well as the intracerebral delivery of potential therapeutic drugs undergoing a preclinical investigation. The method is also ethically favorable as animal pain and distress or disability are controlled and relatively minimal. The expected timeframe for the implementation of the entire protocol is around 8 - 10 weeks.

The combination of computer-aided design (CAD) techniques based on computed tomography (CT) data to generate patient-specific implants is in use for decades. However, persisting disadvantages are complicated design procedures and rigid reconstruction protocols, for example, for tailored implants mimicking the patient-specific thickness distribution of missing cranial bone. In this study we used two different approaches, CAD- versus thin-plate spline (TPS)-based implants, to reconstruct extensive unilateral and bilateral cranial defects in three clinical cases. We used CT data of three complete human crania that were virtually damaged according to the missing regions in the clinical cases. In total, we carried out 132 virtual reconstructions and quantified accuracy from the original to the generated implant and deviations in the resulting implant thickness as root-mean-square error (RMSE). Reconstructions using TPS showed an RMSE of 0.08-0.18 mm in relation to geometric accuracy. CAD-based implants showed an RMSE of 0.50-1.25 mm. RMSE in relation to implant thickness was between 0.63 and 0.70 mm (TPS) while values for CAD-based implants were significantly higher (0.63-1.67 mm). While both approaches provide implants showing a high accuracy, the TPS-based approach additionally provides implants that accurately reproduce the patient-specific thickness distribution of the affected cranial region.

In this article, we present a skull database containing 500 healthy skulls segmented from high-resolution head computed-tomography (CT) scans and 29 defective skulls segmented from craniotomy head CTs. Each healthy skull contains the complete anatomical structures of human skulls, including the cranial bones, facial bones and other subtle structures. For each craniotomy skull, a part of the cranial bone is missing, leaving a defect on the skull. The defects have various sizes, shapes and positions, depending on the specific pathological conditions of each patient. Along with each craniotomy skull, a cranial implant, which is designed manually by an expert and can fit with the defect, is provided. Considering the large volume of the healthy skull collection, the dataset can be used to study the geometry/shape variabilities of human skulls and create a robust statistical model of the shape of human skulls, which can be used for various tasks such as cranial implant design. The craniotomy collection can serve as an evaluation set for automatic cranial implant design algorithms.

Database of 500 High-resolution Healthy Human Skulls and 29 Craniotomy Skulls and Implants. If you use any part of the dataset, please use the following references for citation in your work: Li J., et al. MUG500+ Repository. Figshare, 2021. DOI: 10.6084/m9.figshare.9616319 Li J., et al. MUG500+: Database of 500 High-resolution Healthy Human Skulls and 29 Craniotomy Skulls and Implants. Data in Brief, Elsevier, 2021. A recorded tutorial video about the semi-automatic cranial implant design workflow with Geomagic Sculpt can be viewed at: https://www.youtube.com/watch?v=FzaR3ydjaSc

Successful treatment of glioblastoma multiforme (GBM), the most lethal tumor of the brain, is presently hampered by (i) the limits of safe surgical resection and (ii) “shielding” of residual tumor cells from promising chemotherapeutic drugs such as Gemcitabine (Gem) by the blood brain barrier (BBB). Here, the vastly greater GBM cell‐killing potency of Gem compared to the gold standard temozolomide is confirmed, moreover, it shows neuronal cells to be at least 10 4 ‐fold less sensitive to Gem than GBM cells. The study also demonstrates the potential of an electronically‐driven organic ion pump (“GemIP”) to achieve controlled, targeted Gem delivery to GBM cells. Thus, GemIP‐mediated Gem delivery is confirmed to be temporally and electrically controllable with pmol min −1 precision and electric addressing is linked to the efficient killing of GBM cell monolayers. Most strikingly, GemIP‐mediated GEM delivery leads to the overt disintegration of targeted GBM tumor spheroids. Electrically‐driven chemotherapy, here exemplified, has the potential to radically improve the efficacy of GBM adjuvant chemotherapy by enabling exquisitely‐targeted and controllable delivery of drugs irrespective of whether these can cross the BBB.