A Novel Approach to Virtual Surgical Planning for Mandibular and Midfacial Reconstruction With a Fibula Free Flap.

BACKGROUND: The fibula free flap is a major workhorse in facial reconstruction. To decrease operative times, virtual surgical planning (VSP) has been implemented. Traditional VSP is costly and may delay operative planning. in this study, the authors present a novel algorithm using readily accessible software packages to perform VSP in a manner that is quick and cost-effective. METHODS: A 6-part survey was administered to physicians with prior training in facial reconstruction. Fourteen physicians participated regarding outcomes on 10 patients who underwent mandibular or midfacial fibula free flap reconstruction. Participants were asked to match the true postoperative and VSP models and rate the similarity of the models using the Likert scale (0-10). The goal was to determine whether the VSP models accurately depicted the actual reconstruction, and whether they would use VSP in future clinical practice. RESULTS: The physicians surveyed were able to match the models correctly 93.6% of the time. The mean score for the similarity between virtual and actual models ranged between 7.60 and 8.80. Most participants (90.9%) who answered stated they would use our VSP algorithm if they were trained in the protocol. CONCLUSIONS AND RELEVANCE: Virtual surgical planning models were created utilizing our novel algorithm. Participants matched the preoperative VSP plan with the postoperative model most of the time and rated the similarity well. Participants in our study are interested in learning more about physician performed VSP. The authors believe this model may be financially and clinically relevant and serve as an excellent educational tool.

New and emerging patient-centered CT imaging and image-guided treatment paradigms for maxillofacial trauma.

This article reviews the conceptual framework, available evidence, and practical considerations pertaining to nascent and emerging advances in patient-centered CT-imaging and CT-guided surgery for maxillofacial trauma. These include cinematic rendering-a novel method for advanced 3D visualization, incorporation of quantitative CT imaging into the assessment of orbital fractures, low-dose CT imaging protocols made possible with contemporary scanners and reconstruction techniques, the rapidly growing use of cone-beam CT, virtual fracture reduction with design software for surgical pre-planning, the use of 3D printing for fabricating models and implants, and new avenues in CT-guided computer-aided surgery.

3D Printing Prototypes for Healthcare Professionals: Creating a Reciprocating Syringe.

3D printing (additive manufacturing) has been around since 1984, but interest in the technology has increased exponentially as it has become both accessible and inexpensive. The applications of the technology in healthcare are still being explored; however, initial forays have been encouraging. It has the potential to revolutionize the process of prototyping for healthcare professionals by democratizing the process and enhancing collaboration, making it cheaper to do iterative prototyping with little or no engineering experience. This case report details the creation of a multi-lumen reciprocating syringe with 3D printing. The product has been created and tested using a variety of publicly available resources. It provides a detailed overview of the approach and the framework required to create such a medical device. However, the implications of this report are much larger than this one product, and the fundamental ideas discussed here could be used for creating customized solutions for many healthcare problems.

We Built This House; It's Time to Move in: Leveraging Existing DICOM Structure to More Completely Utilize Readily Available Detailed Contrast Administration Information.

The Digital Imaging and Communications in Medicine (DICOM) standard is the universal format for interoperability in medical imaging. In addition to imaging data, DICOM has evolved to support a wide range of imaging metadata including contrast administration data that is readily available from many modern contrast injectors. Contrast agent, route of administration, start and stop time, volume, flow rate, and duration can be recorded using DICOM attributes [1]. While this information is sparsely and inconsistently recorded in routine clinical practice, it could potentially be of significant diagnostic value. This work will describe parameters recorded by automatic contrast injectors, summarize the DICOM mechanisms available for tracking contrast injection data, and discuss the role of such data in clinical radiology.

Development of a patient specific cartilage graft using magnetic resonance imaging and 3D printing.

OBJECTIVES: The goal of this project was to develop and validate a patient-specific, anatomically correct graft for cartilage restoration using magnetic resonance imaging (MRI) data and 3-dimensional (3D) printing technology. The specific aim was to test the accuracy of a novel method for 3D printing and implanting individualized, anatomically shaped bio-scaffolds to treat cartilage defects in a human cadaveric model. We hypothesized that an individualized, anatomic 3D-printed scaffold designed from MRI data would provide a more optimal fill for a large cartilage defect compared to a generic flat scaffold. METHODS: Four focal cartilage defects (FCDs) were created in paired human cadaver knees, age <40 years, in the weight-bearing surfaces of the medial femoral condyle (MFC), lateral femoral condyle (LFC), patella, and trochlea of each knee. MRIs were obtained, anatomic grafts were designed and 3D printed for the left knee as an experimental group, and generic flat grafts for the right knee as a control group. Grafts were implanted into corresponding defects and fixed using tissue adhesive. Repeat post-implant MRIs were obtained. Graft step-off was measured as the distance in mm between the surface of the graft and the native cartilage surface in a direction perpendicular to the subchondral bone. Graft contour was measured as the gap between the undersurface of the graft and the subchondral bone in a direction perpendicular to the joint surface. RESULTS: Graft step-off was statistically significantly better for the anatomic grafts compared to the generic grafts in the MFC (0.0 â€‹± â€‹0.2 â€‹mm vs. 0.7 â€‹± â€‹0.5 â€‹mm, p â€‹< â€‹0.001), LFC (0.1 â€‹± â€‹0.3 â€‹mm vs. 1.0 â€‹± â€‹0.2 â€‹mm, p â€‹< â€‹0.001), patella (-0.2 â€‹± â€‹0.3 â€‹mm vs. -1.2 â€‹± â€‹0.4 â€‹mm, p â€‹< â€‹0.001), and trochlea (-0.4 â€‹± â€‹0.3 vs. 0.4 â€‹± â€‹0.7, p â€‹= â€‹0.003). Graft contour was statistically significantly better for the anatomic grafts in the LFC (0.0 â€‹± â€‹0.0 â€‹mm vs. 0.2 â€‹± â€‹0.4 â€‹mm, p â€‹= â€‹0.022) and trochlea (0.0 â€‹± â€‹0.0 â€‹mm vs. 1.4 â€‹± â€‹0.7 â€‹mm, p â€‹< â€‹0.001). The anatomic grafts had an observed maximum step-off of -0.9 â€‹mm and a maximum contour mismatch of 0.8 â€‹mm. CONCLUSION: This study validates a process designed to fabricate anatomically accurate cartilage grafts using MRI and 3D printing technology. Anatomic grafts demonstrated superior fit compared to generic flat grafts. LEVEL OF EVIDENCE: Level IV.

Demographics, utilization, workflow and outcomes based on observational data from the RSNA-ACR 3D Printing Registry.

OBJECTIVE: To report data from the first three years of operation of the RSNA-ACR 3D Printing Registry. METHODS: Data from June 2020 to June 2023 was extracted, including demographics, indications, workflow and user assessments. Clinical indications were stratified by 12 organ systems. Imaging modalities, printing technologies and number of parts per case were assessed. Effort data was analyzed, dividing staff into provider and non-provider categories. The opinions of clinical users were evaluated through a Likert-scale questionnaire, and estimates of procedure time saved were collected. RESULTS: A total of 20 sites and 2,637 cases were included, consisting of 1,863 anatomic models and 774 anatomic guides. Mean patient age for models and guides was 42.4 ± 24.5 years and 56.3 ± 18.5 years respectively. Cardiac models were the most common type of models (27.2%), and neurologic guides were the most common type of guides (42.4%). Material jetting, vat photopolymerization and material extrusion were the most common printing technologies used overall (85.6% of all cases). On average, providers spent 92.4 minutes and non-providers spent 335.0 minutes per case. Providers spent most time on consultation (33.6 minutes), while non-providers focused most on segmentation (148.0 minutes). Confidence in treatment plans increased after using 3D printing (p<.001). Estimated procedure time savings for 155 cases was 40.5 ± 26.1 minutes. CONCLUSION: 3D printing is performed in healthcare facilities for many clinical indications. The registry provides insight into the technologies and workflows used to create anatomic models and guides, and the data shows clinical benefits from 3D printing.

Anatomical Differences Between Human and Pig Hearts and Their Relevance for Cardiac Xenotransplantation Surgical Technique.

Cardiac xenotransplantation has been proposed to bridge the gap between supply and demand for patients with end-stage heart failure requiring transplantation. However, differences in pig anatomy compared with human anatomy require modification of the surgical approach. In addition, careful consideration should be given to size matching before transplantation. (Level of Difficulty: Advanced.).

Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase.

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.

Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.

A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.

Expression, purification, and characterization of TYK-2 kinase domain, a member of the Janus kinase family.

The Janus kinase family consists of four members: JAK-1, -2, -3 and TYK-2. While JAK-2 and JAK-3 have been well characterized biochemically, there is little data on TYK-2. Recent work suggests that TYK-2 may play a critical role in the development of a number of inflammatory processes. We have carried out a series of biochemical studies to better understand TYK-2 enzymology and its inhibition profile, in particular how the TYK-2 phosphorylated forms differ from each other and from the other JAK family members. We have expressed and purified milligram quantities of the TYK-2 kinase domain (KD) to high purity and developed a method to separate the non-, mono- (pY(1054)) and di-phosphorylated forms of the enzyme. Kinetic studies (k(cat(app))/K(m(app))) indicated that phosphorylation of the TYK-2-KD (pY(1054)) increased the catalytic efficiency 4.4-fold compared to its non-phosphorylated form, while further phosphorylation to generate the di-phosphorylated enzyme imparted no further increase in activity. These results are in contrast to those obtained with the JAK-2-KD and JAK-3-KD, where little or no increase in activity occurred upon mono-phosphorylation, while di-phosphorylation resulted in a 5.1-fold increase in activity for the JAK-2-KD. Moreover, ATP-competitive inhibitors demonstrated 10-30-fold shifts in potency (K(i(app))) as a result of the TYK-2-KD phosphorylation state, while the shifts for JAK-3-KD were only 2-3-fold and showed little or no change for JAK-2-KD. Thus, the phosphorlyation state imparted differential effects on both activity and inhibition within the JAK family of kinases.

A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation.

Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacologic properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compound that inhibits MK2 activity (K(i) = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFalpha production with similar activity (IC(50) = 160 nM). PF-3644022 blocks TNFalpha and IL-6 production in LPS-stimulated human whole blood with IC(50) values of 1.6 and 10.3 microM, respectively. Inhibition of TNFalpha in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFalpha model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFalpha production in the acute model and inhibition of paw swelling in the chronic model is observed with ED(50) values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a C(min) higher than the EC(50) measured in the rat LPS-induced TNFalpha model.

Expression, purification, characterization and crystallization of non- and phosphorylated states of JAK2 and JAK3 kinase domain.

Janus-associated kinases (JAKs) play critical roles in cytokine signaling, and have emerged as viable therapeutic targets in inflammation and oncology related diseases. To date, targeting JAK proteins with highly selective inhibitor compounds have remained elusive. We have expressed the active kinase domains for both JAK2 and JAK3 and devised purification protocols to resolve the non-, mono- (Y1007) and diphosphorylated (Y1007 and Y1008) states of JAK2 and non- and monophosphorylated states of JAK3 (Y980). An optimal purified protein yield of 20, 29 and 69mg per 20L cell culture was obtained for the three JAK2 forms, respectively, and 12.2 and 2.3mg per 10L fermentation for the two JAK3 forms allowing detailed biochemical and biophysical studies. To monitor the purification process we developed a novel HPLC activity assay where a sequential order of phosphorylation was observed whereby the first tyrosine residue was completely phosphorylated prior to phosphorylation of the tandem tyrosine residue. A Caliper-based microfluidics assay was used to determine the kinetic parameters (K(m) and k(cat)) for each phosphorylated state, showing that monophosphorylated (Y1007) JAK2 enzyme activity increased 9-fold over that of the nonphosphorylated species, and increased an additional 6-fold for the diphosphorylated (Y1007/Y1008) species, while phosphorylation of JAK3 resulted in a negligible increase in activity. Moreover, crystal structures have been generated for each isolated state of JAK2 and JAK3 with resolutions better than 2.4A. The generation of these reagents has enabled kinetic and structural characterization to inform the design of potent and selective inhibitors of the JAK family.

A Mass Spectrometric Assay of METTL3/METTL14 Methyltransferase Activity.

A variety of covalent modifications of RNA have been identified and demonstrated to affect RNA processing, stability, and translation. Methylation of adenosine at the N6 position (m6A) in messenger RNA (mRNA) is currently the most well-studied RNA modification and is catalyzed by the RNA methyltransferase complex METTL3/METTL14. Once generated, m6A can modulate mRNA splicing, export, localization, degradation, and translation. Although potent and selective inhibitors exist for several members of the Type I S-adenosylmethionine (SAM)-dependent methyltransferase family, no inhibitors have been reported for METTL3/METTL14 to date. To facilitate drug discovery efforts, a sensitive and robust mass spectrometry-based assay for METTL3/METTL14 using self-assembled monolayer desorption/ionization (SAMDI) technology has been developed. The assay uses an 11-nucleotide single-stranded RNA compared to a previously reported 27-nucleotide substrate. IC50 values of mechanism-based inhibitors S-adenosylhomocysteine (SAH) and sinefungin (SFG) are comparable between the SAMDI and radiometric assays that use the same substrate. This work demonstrates that SAMDI technology is amenable to RNA substrates and can be used for high-throughput screening and compound characterization for RNA-modifying enzymes.

Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804.

PH-797804 is a diarylpyridinone inhibitor of p38alpha mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. On the basis of structural comparison with a different biaryl pyrazole template and supported by dozens of high-resolution crystal structures of p38alpha inhibitor complexes, PH-797804 is predicted to possess a high level of specificity across the broad human kinase genome. We used a structural bioinformatics approach to identify two selectivity elements encoded by the TXXXG sequence motif on the p38alpha kinase hinge: (i) Thr106 that serves as the gatekeeper to the buried hydrophobic pocket occupied by 2,4-difluorophenyl of PH-797804 and (ii) the bidentate hydrogen bonds formed by the pyridinone moiety with the kinase hinge requiring an induced 180 degrees rotation of the Met109-Gly110 peptide bond. The peptide flip occurs in p38alpha kinase due to the critical glycine residue marked by its conformational flexibility. Kinome-wide sequence mining revealed rare presentation of the selectivity motif. Corroboratively, PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. PH-797804 has met safety criteria in human phase I studies and is under clinical development for several inflammatory conditions. Understanding the rationale for selectivity at the molecular level helps elucidate the biological function and design of specific p38alpha kinase inhibitors.

Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation.

Signal transduction through the p38 mitogen-activated protein (MAP) kinase pathway is central to the transcriptional and translational control of cytokine and inflammatory mediator production. p38 MAP kinase inhibition hence constitutes a promising therapeutic strategy for treatment of chronic inflammatory diseases, based upon its potential to inhibit key pathways driving the inflammatory and destructive processes in these debilitating diseases. The present study describes the pharmacological properties of the N-phenyl pyridinone p38 MAP kinase inhibitor benzamide [3- [3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2- oxo-1(2H)-pyridinyl]-N,4-dimethyl-, (-)-(9CI); PH-797804]. PH-797804 is an ATP-competitive, readily reversible inhibitor of the alpha isoform of human p38 MAP kinase, exhibiting a K(i) = 5.8 nM. In human monocyte and synovial fibroblast cell systems, PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E(2), at concentrations that parallel inhibition of cell-associated p38 MAP kinase. After oral dosing, PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. Furthermore, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Finally, PH-797804 reduced tumor necrosis factor-alpha and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme. Low-nanomolar biochemical enzyme inhibition potency correlated with p38 MAP kinase inhibition in human cells and in vivo studies. In addition, a direct correspondence between p38 MAP kinase inhibition and anti-inflammatory activity was observed with PH-797804, thus providing confidence in dose projections for further human studies in chronic inflammatory disease.

SD0006: a potent, selective and orally available inhibitor of p38 kinase.

SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38alpha activity and that of lipopolysaccharide-stimulated TNFalpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC(50)) for inhibiting tumor necrosis factor-alpha (TNFalpha) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFalpha treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.

Deciphering the Allosteric Binding Mechanism of the Human Tropomyosin Receptor Kinase A ( hTrkA) Inhibitors.

Access to cryptic binding pockets or allosteric sites on a kinase that present themselves when the enzyme is in a specific conformational state offers a paradigm shift in designing the next generation small molecule kinase inhibitors. The current work showcases an extensive and exhaustive array of in vitro biochemical and biophysical tools and techniques deployed along with structural biology efforts of inhibitor-bound kinase complexes to characterize and confirm the cryptic allosteric binding pocket and docking mode of the small molecule actives identified for hTrkA. Specifically, assays were designed and implemented to lock the kinase in a predominantly active or inactive conformation and the effect of the kinase inhibitor probed to understand the hTrkA binding and hTrkB selectivity. The current outcome suggests that inhibitors with a fast association rate take advantage of the inactive protein conformation and lock the kinase state by also exhibiting a slow off-rate. This in turn shifts the inactive/active state protein conformational equilibrium cycle, affecting the subsequent downstream signaling.

Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals.

p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1ß expression by promoting IL-1ß mRNA degradation. Thus, IL-1ß is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α-MK2. CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38α inhibitors in attenuating arthritis in rats and cytokine expression by cells from patients with cryopyrinopathy and rheumatoid arthritis. These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with global p38α inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.

Surgical reconstruction of the ossicular chain with custom 3D printed ossicular prosthesis.

BACKGROUND: Conductive hearing loss due to ossicular abnormalities occurs from many causes, including trauma, infection, cholesteatoma, surgery and congenital anomalies. Surgical reconstruction of the ossicular chain is a well-established procedure for repair of ossicular defects, but is still plagued by high failure rates. Underlying disease and proper sizing of prostheses are two challenges that lead to component failure. Three-dimensional (3D) printing has been used successfully to solve a number of medical prosthesis problems. Custom 3D printing an individualized ossicular prosthesis would be a potential solution for the wide range of anatomic variation encountered in the pathological middle ear, and could decrease the rate of post-operative prosthesis displacement by increasing the likelihood of a proper fit, in addition to decreasing surgical time.In this study, the incus was removed from three formalin-fixed cadaveric human temporal bones with no macro- or microscopic evidence of pathology. Imaging of the cadaveric bone was obtained using a standard temporal bone CT protocol. A custom prosthesis for each cadaveric human temporal bone was designed using the Mimics Innovation Suite software (Materialise, Belgium) and fabricated on a Form2 3D printer (FormLabs, Somerville, Massachusetts). Four surgeons then performed insertion of each prosthesis into each middle ear, blinded to the bone from and for which each was designed. The surgeons were asked to match each prosthesis to its correct parent bone. RESULTS: Each prosthesis had unique measurements. Each of the four surgeons was able to correctly match the prosthesis model to its intended temporal bone. The chances of this occurring randomly are 1:1296. CONCLUSIONS: A custom 3D printed ossicular prosthesis is a viable solution for conductive hearing loss due to ossicular chain defects. Commercially available CT scanners can detect significant anatomic differences in normal human middle ear ossicles. These differences can be accurately represented with current 3D printing technology and, more significantly, surgeons can detect these differences.