Combined inverse-forward artificial neural networks for fast and accurate estimation of the diffusion coefficients of cartilage based on multi-physics models

Analytical and numerical methods have been used to extract essential engineering parameters such as elastic modulus, Poisson's ratio, permeability and diffusion coefficient from experimental data in various types of biological tissues. The major limitation associated with analytical techniques is that they are often only applicable to problems with simplified assumptions. Numerical multi-physics methods, on the other hand, enable minimizing the simplified assumptions but require substantial computational expertise, which is not always available. In this paper, we propose a novel approach that combinesinverse and forward artificial neural networks (ANNs) which enables fast and accurate estimation of the diffusion coefficient of cartilage without any need for computational modeling. In this approach, an inverse ANN is trained using our multi-zone biphasic-solute finite-bath computational model of diffusionin cartilage to estimate the diffusion coefficient of the various zones of cartilage given the concentrationtime curves. Robust estimation of the diffusion coefficients, however, requires introducing certain levels of stochastic variations during the training process. Determining the required level of stochastic variation is performed by coupling the inverse ANN with a forward ANN that receives the diffusion coefficient as input and returns the concentration-time curve as output. Combined together, forward-inverse ANNs enable computationally inexperienced users to obtain accurate and fast estimation of the diffusion coefficients of cartilage zones. The diffusion coefficients estimated using the proposed approach are compared with those determined using direct scanning of the parameter space as the optimization approach. It has been shown that both approaches yield comparable results.Accepted Authors ManuscriptBiomaterials & Tissue Biomechanic

Fractures in Osteogenesis Imperfecta: Pathogenesis, Treatment, Rehabilitation and Prevention

Fractures in patients with osteogenesis imperfecta (OI) are caused by a decreased strength of bone due to a decreased quality and quantity of bone matrix and architecture. Mutations in the collagen type 1 encoding genes cause the altered formation of collagen type I, one of the principal building blocks of bone tissue. Due to the complexity of the disease and the high variation of the clinical problems between patients, treatment for these patients should be individually tailored. In general, short immobilization periods with flexible casting material, use of intramedullary implants, and simultaneous deformity correction are preferred. Multidisciplinary care with a broad view of the support needed for the patient and his/her living environment is necessary for the optimal rehabilitation of these patients. Increasing bone strength with exercise, medication, and sometimes alignment surgery is generally indicated to prevent fractures.Biomaterials & Tissue Biomechanic

The impact of immune response on endochondral bone regeneration

Tissue engineered cartilage substitutes, which induce the process of endochondral ossification, represent a regenerative strategy for bone defect healing. Such constructs typically consist of multipotent mesenchymal stromal cells (MSCs) forming a cartilage template in vitro, which can be implanted to stimulate bone formation in vivo. The use of MSCs of allogeneic origin could potentially improve the clinical utility of the tissue engineered cartilage constructs in three ways. First, ready-to-use construct availability can speed up the treatment process. Second, MSCs derived and expanded from a single donor could be applied to treat several patients and thus the costs of the medical interventions would decrease. Finally, it would allow more control over the quality of the MSC chondrogenic differentiation. However, even though the envisaged clinical use of allogeneic cell sources for bone regeneration is advantageous, their immunogenicity poses a significant obstacle to their clinical application. The aim of this review is to increase the awareness of the role played by immune cells during endochondral ossification, and in particular during regenerative strategies when the immune response is altered by the presence of implanted biomaterials and/or cells. More specifically, we focus on how this balance between immune response and bone regeneration is affected by the implantation of a cartilaginous tissue engineered construct of allogeneic origin.Biomaterials & Tissue Biomechanic

Rationally designed meta-implants: a combination of auxetic and conventional meta-biomaterials

Rationally designed meta-biomaterials present unprecedented combinations of mechanical, mass transport, and biological properties favorable for tissue regeneration. Here we introduce hybrid meta-biomaterials with rationally-distributed values of negative (auxetic) and positive Poisson’s ratios, and use them to design meta-implants that unlike conventional implants do not retract from the bone under biomechanical loading. We rationally design and additively manufacture six different types of meta-biomaterials (three auxetic and three conventional), which then serve as the parent materials to six hybrid meta-biomaterials (with or without transitional regions). Both single and hybrid meta-biomaterials are mechanically tested to reveal their full-field strain distribution by digital image correlation. The best-performing hybrid metabiomaterials are then selected for the design of meta-implants (hip stems), which are tested under simulated-implantation conditions.Full-field strain measurements clearly show that, under biomechanical loading, hybrid meta-implants press onto the bone on both the medial and lateral sides, thereby improving implant–bone contact and potentially implant longevity.Biomaterials & Tissue Biomechanic

Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies.Biomaterials & Tissue Biomechanic

Bone regeneration in critical-sized bone defects treated with additively manufactured porous metallic biomaterials: The effects of inelastic mechanical properties

Additively manufactured (AM) porous metallic biomaterials, in general, and AM porous titanium, in particular, have recently emerged as promising candidates for bone substitution. The porous design of such materials allows for mimicking the elastic mechanical properties of native bone tissue and showed to be effective in improving bone regeneration. It is, however, not clear what role the other mechanical properties of the bulk material such as ductility play in the performance of such biomaterials. In this study, we compared the bone tissue regeneration performance of AM porous biomaterials made from the commonly used titanium alloy Ti6Al4V-ELI with that of commercially pure titanium (CP-Ti). CP-Ti was selected because of its high ductility as compared to Ti6Al4V-ELI. Critical-sized (6 mm diameter) femoral defects in rats were treated with implants made from both Ti6Al4V-ELI and CP-Ti. Bone regeneration was assessed up to 11 weeks using micro-CT scanning. The regenerated bone volume was assessed ex vivo followed by histology and biomechanical testing to assess osseointegration of the implants. The bony defects treated withAMCP-Ti implants generally showed higher volumes of regenerated bone as compared to those treated with AM Ti6Al4V-ELI. The torsional strength of the two titanium groups were similar however, and both considerably lower than those measured for intact bony tissue. These findings show the importance of material type and ductility of the bulk material in the ability for bone tissue regeneration of AM porous biomaterials.Biomaterials & Tissue Biomechanic

Groove model of tibia-femoral osteoarthritis in the rat

Several experimental models of osteoarthritis in rats are used to study the pathophysiology of osteoarthritis. Many mechanically induced models have the limitation that permanent joint instability is induced by, for example, ligament transection or meniscal damage. This permanent instability will counteract the potential beneficial effects of therapy. The groove model of osteoarthritisuses a one-time trigger, surgically induced cartilage damage on the femoral condyles, and has been validated for the canine tibia-femoral compartment. The present study evaluates this model for the rat knee joint. The articular cartilage of the weight bearing surface of both femoral condyles and trochlea were damaged (grooved) without damaging the underlying subchondral bone. Severity of joint degeneration was histologically assessed, in addition to patella cartilage damage, and subchondral bone characteristics by means of (contrast-enhanced) micro-CT. Mild histological degeneration of the surgically untouched tibial plateau cartilage was observed in addition to damage of the femoral condyles, without clear synovial tissue inflammation. Contrast enhanced micro-CT demonstrated proteoglycan loss of the surgically untouched patella cartilage. Besides, a more sclerotic structure of the subchondral bone was observed. The tibiafemoral groove model in a rat results in mild knee joint degeneration, without permanent joint instability and joint inflammation. This makes the rat groove model a useful model to study the onset and progression of post-traumatic non-inflammatory osteoarthritis, creating a relatively sensitive model to study disease modifying osteoarthritic drugs. 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res.Biomaterials & Tissue Biomechanic

Additively manufactured metallic porous biomaterials based on minimal surfaces: A unique combination of topological, mechanical, and mass transport properties

Porous biomaterials that simultaneously mimic the topological, mechanical, and mass transport properties of bone are in great demand but are rarely found in the literature. In this study, we rationally designed and additively manufactured (AM) porous metallic biomaterials based on four different types of triply periodic minimal surfaces (TPMS) that mimic the properties of bone to an unprecedented level of multi-physics detail. Sixteen different types of porous biomaterials were rationally designed and fabricated using selective laser melting (SLM) from a titanium alloy (Ti-6Al-4V). The topology, quasi-static mechanical properties, fatigue resistance, and permeability of the developed biomaterials were then characterized. In terms of topology, the biomaterials resembled the morphological properties of trabecular bone including mean surface curvatures close to zero. The biomaterials showed a favorable but rare combination of relatively low elastic properties in the range of those observed for trabecular bone and high yield strengths exceeding those reported for cortical bone. This combination allows for simultaneously avoiding stress shielding, while providing ample mechanical support for bone tissue regeneration and osseointegration. Furthermore, as opposed to other AM porous biomaterials developed to date for which the fatigue endurance limit has been found to be ≈20% of their yield (or plateau) stress, some of the biomaterials developed in the current study show extremely high fatigue resistance with endurance limits up to 60% of their yield stress. It was also found that the permeability values measured for the developed biomaterials were in the range of values reported for trabecular bone. In summary, the developed porous metallic biomaterials based on TPMS mimic the topological, mechanical, and physical properties of trabecular bone to a great degree. These properties make them potential candidates to be applied as parts of orthopedic implants and/or as bone-substituting biomaterials.Accepted Author ManuscriptBiomaterials & Tissue Biomechanic

Challenges in the design and regulatory approval of 3D-printed surgical implants: a two-case series

Background: Additive manufacturing or three-dimensional (3D) printing of metal implants can provide novel solutions for difficult-to-treat conditions, yet legislation concerning patient-specific implants complicates the implementation of these techniques in daily practice. In this Article, we share our acquired knowledge of the logistical and legal challenges associated with the use of patient-specific 3D-printed implants to treat spinal instabilities. Methods: Two patients with semiurgent cases of spinal instability presented to our hospital in the Netherlands. In case 1, severe kyphotic deformity of the thoracic spine due to neurofibromatosis type 1 had led to incomplete paralysis, and a strong metallic strut extending from C6 to T11 was deemed necessary to provide long-term anterior support. In case 2, the patient presented with progressive paralysis caused by cervicothoracic dissociation due to vanishing bone disease. As the C5–T1 vertebral bodies had mostly vanished, an implant spanning the anterior spine from C4 to T2 was required. Because of the complex and challenging nature of both cases, conventional approaches were deemed inadequate; instead, patient-specific implants were designed with use of CT scans and computer-aided design software, and 3D printed in titanium with direct metal printing. For each implant, to ensure patient safety, a comprehensive technical file (describing the clinical substantiation, technical and design considerations, risk analysis, manufacturing process, and labelling) was produced in collaboration with a university department certified for the development and manufacturing of medical devices. Because the implants were categorised as custom-made or personalised devices under the EU Medical Device Regulation, the usual procedures for review and approval of medical devices by a notified body were not required. Finite-element analyses, compression strength tests, and cadaveric experiments were also done to ensure the devices were safe to use. Findings: The planning, design, production, and insertion of the 3D-printed personalised implant took around 6 months in the first patient, but, given the experience from the first case, only took around 6 weeks in the second patient. In both patients, the surgeries went as planned and good positioning of each implant was confirmed. Both patients were discharged home within 1 week after the surgery. In the first patient, a fatigue fracture occured in one of the conventional posterior fusion rods after 10 months, which we repaired, without any deformation of the spine or signs of failure of the personalised implant observed. No other adverse events occurred up to 25 months of follow-up in case 1 and 6 months of follow-up in case 2. Interpretation: Patient-specific treatment approaches incorporating 3D-printed implants can be helpful in carefully selected cases when conventional methods are not an option. Comprehensive and efficient interactions between medical engineers and physicians are essential to establish well designed frameworks to navigate the logistical and regulatory aspects of technology development to ensure the safety and legal validity of patient-specific treatments. The framework described here could encourage physicians to treat (once untreatable) patients with novel personalised techniques. Funding: Interreg VA Flanders—The Netherlands programme, Applied and Engineering Sciences research programme, the Netherlands Organisation for Scientific Research, and the Dutch Arthritis Foundation Video Abstract.Biomaterials & Tissue Biomechanic

Trigonometric algorithm defining the true three-dimensional acetabular cup orientation: Correlation between measured and calculated cup orientation angles

Background: Acetabular cup orientation plays a key role in implant stability and the success of total hip arthroplasty. To date, the orientation has been measured with different imaging modalities and definitions, leading to lack of consensus on optimal cup placement. A 3-dimensional (3D) concept involving a trigonometric description enables unambiguous definitions. Our objective was to test the validity and reliability of a 3D trigonometric description of cuporientation.Methods: Computed tomographic scans of the pelvis, performed for vascular assessment of 20 patients with 22 primary total hip replacements in situ, were systematically collected. On multiplanar reconstructions, 3 observers independently measured cup orientation retrospectively in terms of coronal inclination, sagittal tilt, and transverse version. The angles measured in 2 planes were used to calculate the angle in the third plane via a trigonometric algorithm. For correlation and reliability analyses, intraobserver and interobserver differences between measured and calculated angles were evaluated with use of the intraclass correlation coefficient (ICC).Results: Measured and calculated angles had ICCs of 0.953 for coronal inclination, 0.985 for sagittal tilt, and 0.982 for transverse version. Intraobserver and interobserver reliability had ICCs of 0.987 and 0.987, respectively, for coronal inclination; 0.979 and 0.981, respectively, for sagittal tilt; and 0.992 and 0.978, respectively, for transverse version.Conclusions: The 3D concept with its trigonometric algorithm is a valid and reliable tool for the measurement of cup orientation.Clinical Relevance: By calculating the transverse version of cups from coronal inclination and sagittal tilt measurements, the trigonometric algorithm enables a 3D definition of cup orientation, regardless of the imaging modality used. In addition, it introduces sagittal tilt that, like pelvic tilt, rotates around the transverse axis.Biomaterials & Tissue Biomechanic