From Academia: 3D Printing and Robotics, Stem cell coated Implants, Decentralized Mitigation of Pandemics

This is our weekly selection of recently published academic abstracts focusing on topics 3DHEALS audience would be interested in. Submit your favorite publication to ([email protected])

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Innovation in silos is dangerous. What’s equally unrealistic is to think that 3D printing will be the only force that will save the world. It will not.
Often times, several technologies can work together to create something much more powerful. Several articles in this week’s selection demonstrated the merge of robotics and 3D printing technologies, with various application. One particular fun read was from an Italian group that created a self-growing obstacle avoiding robot that also simultaneous acts as a 3D-printer, enabling a tree-root like growth through an artificial pathway. What healthcare application can you think with that technology? Relating to my recent visit to the Cleveland Clinic, autonomous robotic surgery may not be as far as you can imagine. Another equally intriguing paper was by an Isreali group focusing on decentralized mitigation of world pandemics. This paper has more math than perhaps we want, but it is a serious discussion on how 3D printing can be leveraged in solving public health issues. I have touched upon decentralized healthcare in the past from a different angle. 

Medical 3D Printing

Cleveland Clinic, Ohio, USA

Three-Dimensional Printing Applications in Percutaneous Structural Heart Interventions. (Harb SC, et al) Circ Cardiovasc Imaging. 2019 Oct;12(10):e009014. doi: 10.1161/CIRCIMAGING.119.009014. Epub 2019 Oct 9.

Cardiovascular 3-dimensional printing refers to the fabrication of patients’ specific cardiac anatomic replicas based on volumetric imaging data sets obtained by echocardiography, computed tomography, or magnetic resonance imaging. It enables advanced visualization and enhanced anatomic and sometimes hemodynamic understanding and also improves procedural planning and allows interventional simulation. Also, it is helpful in communication with patients and trainees. These key advantages have led to its broad use in the field of cardiology ranging from congenital to vascular and valvular disease, particularly in structural heart interventions, where many emerging technologies are being developed and tested. This review summarizes the process of 3-dimensional printing and the workflow from imaging acquisition to model generation and discusses the cardiac applications of 3-dimensional printing focusing on its use in percutaneous structural interventions, where procedural planning now commonly relies on 3-dimensional printed models.

Image credit: Harb S.C. et al.

(The figure above: Combining different materials to represent various types of tissues. Different materials may be combined together to represent the different tissue properties. While soft tissue in these examples is printed using flexible material, more rigid material is added to represent calcifications (A), annuloplasty ring (B), and a pacemaker lead (C). In addition, different colors can be combined in the same model representing various structures. In this example (D), left-sided structures are printed in red, while right-sided structures are printed in blue.)

Paris, France

Implementation of a digital chain for the design and manufacture of implant-based surgical guides in a hospital setting.(Thomas P1, et al) J Stomatol Oral Maxillofac Surg. 2019 Oct 5. pii: S2468-7855(19)30222-8. doi: 10.1016/j.jormas.2019.09.009.  

The digital revolution has led to many recent developments in implantology that have considerably facilitated implant planning and the creation of surgical guides. The purpose of this article is to explain how we set up a digital workflow in a large city hospital and how we met the requirements of the European regulations on the production of custom-made devices in a medical establishment. The internal manufacture of a surgical guide complied with European regulation EU/2017/45 concerning medical devices. This regulation allowed the hospital to create these medical devices locally without CE marking. However, the hospital must be declared as a manufacturer of medical devices and comply with the general requirements in terms of safety and performance related to the manufacture and use of medical devices. In addition, hospitals are large structures involving many different actors. Each step of the digital workflow, which included both the patient course and the creation of the surgical guide, was thus adapted to European regulations by considering local constraints.

Louisiana, USA

Improvement of osseointegration by recruiting stem cells to titanium implants fabricated with 3D printing. (Bollman M  , et al) Ann N Y Acad Sci. 2019 Oct 11. doi: 10.1111/nyas.14251. [Epub ahead of print]

Slow and incomplete osseointegration and loss of osseointegration are major problems in dental and bone implants. We designed implants with interconnected 3D-tubulous structures and hypothesized that such interconnecting 3D (I3D) structures would serve as a repository for chemo-attractants to recruit stem cells to promote osseointegration. A concept Laser Mlab-cusing-R laser-powder-bed-fusion (LPBF) 3D printing system was used to produce titanium implants with designed features. The implants were loaded (coated) with stromal cell-derived factor-1 alpha (SDF-1α),  and subjected to stem cell recruitment. Implants were then surgically transplanted into the rabbit skull bone. After 12 weeks, osseointegration was analyzed by reverse-torque test and the implants were examined for calcium deposition by Alizarin Red staining. The I3D implants attracted significantly more stem cells than solid implants when coated (loaded) with SDF-1α. Greater torque force was needed to extract the I3D implants with 200 and 300 µm I3D structures than to extract solid implants from the skull. Generally, more calcium deposition was observed on the I3D implants than on the solid counterparts. LPBF 3D printing can be used to fabricate implants with complex structures. I3D-tubulous structures of implants can retain chemoattractant for recruitment of stem cells to enhance osseointegration.

Guangdong, CHINA

Immobilization of BMP-2-derived peptides on 3D-printed porous scaffolds for enhanced osteogenesis. (Zhang X, et al) Biomed Mater. 2019 Oct 9. doi: 10.1088/1748-605X/ab4c78.

Three-dimensional (3D) printing technologies open new perspectives for customizing the external shape together with the internal architecture of bone scaffolds. In this study, an oligopeptide (SSVPT, Ser-Ser-Val-Pro-Thr) derived from bone morphogenetic protein 2 was conjugated with a dopamine coating of a 3D printed poly(lactic acid) (PLA) scaffold to enhance osteogenesis. Cell experiments in vitro showed that the scaffold was highly osteoconductive to the adhesion and proliferation of rat marrow mesenchymal stem cells (MSCs). In addition, RT-PCR analysis showed that the scaffold could promote the expression of osteogenesis-related genes, such as alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osteopontin (OPN). Images of micro-CT 3D reconstruction from the rat cranial bone defects model showed that bone regeneration patterns occurred from one side edge towards the center of the area implanted with the prepared biomimetic peptide hydrogels, demonstrating significantly accelerated bone regeneration. This work will provide a basis to explore further the application potential of this bioactive scaffold.

Vienna, Austria.

An anthropomorphic phantom representing a prematurely born neonate for digital x-ray imaging using 3D printing: Proof of concept and comparison of image quality from different systems.

(Irnstorfer N1, et al) Sci Rep. 2019 Oct 7;9(1):14357. doi: 10.1038/s41598-019-50925-3.

An anthropomorphic phantom for image optimization in neonatal radiography was developed, and its usability in optimizing image acquisition and processing demonstrated. The phantom was designed to mimic a patient image of a prematurely born neonate. A clinical x-ray (neonate <1 kg) taken with an effective dose of 11 µSv on a needle-crystal storage phosphor system was retrospectively selected from anonymized images as an appropriate template representing a standard case in neonatology imaging. The low dose level used in clinical imaging results in high image noise content. Therefore, the image had to be processed using structure preserving noise reduction. Pixel values were related to printing material thickness to result in a similar attenuation pattern as the original patient including support mattress. A 3D model generating a similar x-ray attenuation pattern on an image detector as a patient was derived accounting for beam hardening and perspective, and printed using different printing technologies. Best printing quality was achieved using a laser stereolithography printer. Phantom images from different digital radiography systems used in neonatal imaging were compared. Effects of technology, image processing, and radiation dose on diagnostic image quality can be assessed for otherwise identical anthropomorphic neonatal images not possible with patient images, facilitating optimization and standardization of imaging parameters and image appearance.

Mannheim, Germany

CT and MRI compatibility of flexible 3D printed materials for soft actuators and robots used in image-guided interventions.

(Neumann W1, et al) 2019 Oct 6. doi: 10.1002/mp.13852.  

PURPOSE:

3D printing allows for the fabrication of medical devices with complex geometries, such as soft actuators and robots that can be used in image-guided interventions. This study investigates flexible and rigid 3D printing materials in terms of their impact on multimodal medical imaging.

METHODS:

The generation of artifacts in clinical CT and MR imaging was evaluated for six flexible and three rigid materials, each with a cubical and a cylindrical geometry, and for one exemplary flexible fluidic actuator. Additionally, CT Hounsfield units (HU) were quantified for various parameter sets iterating peak voltage, X-ray tube current, slice thickness and convolution kernel.

RESULTS:

We found the image artifacts caused by the materials to be negligible in both CT and MR images. The HU values mainly depended on the elemental composition of the materials and applied peak voltage ranging between 80 kVp to 140 kVp. Flexible, non-silicone-based materials ranged between 51 HU and 114 HU. The voltage dependency was less than 29 HU. Flexible, silicone-based materials ranged between 60 HU and 365 HU. The voltage-dependent influence was as large as 172 HU. Rigid materials ranged between -69 HU and 132 HU. The voltage-dependent influence was less than 33 HU.

CONCLUSION:

All tested materials may be employed for devices placed in the field of view during CT and MR imaging as no significant artifacts were measured. Moreover, the material selection in CT could be based on the desired visibility of the material depending on the application. Given the wide availability of the tested materials, we expect our results to have a positive impact on the development of devices and robots for image-guided interventions.

London, United Kingdom

Improved co-registration of ex-vivo and in-vivo cardiovascular magnetic resonance images using heart-specific flexible 3D printed acrylic scaffold combined with non-rigid registration.

(Whitaker J, et al). J Cardiovasc Magn Reson. 2019 Oct 10;21(1):62. doi: 10.1186/s12968-019-0574-z.

BACKGROUND:

Ex-vivo cardiovascular magnetic resonance (CMR) imaging has played an important role in the validation of in-vivo CMR characterization of pathological processes. However, the comparison between in-vivo and ex-vivo imaging remains challenging due to the shape changes occurring between the two states, which may be non-uniform across the diseased heart. A novel two-step process to facilitate registration between ex-vivo and in-vivo CMR was developed and evaluated in a porcine model of chronic myocardial infarction (MI).

METHODS:

Seven weeks after ischemia-reperfusion MI, 12 swine underwent in-vivo CMR imaging with late gadolinium enhancement followed by ex-vivo CMR 1 week later. Five animals comprised the control group, in which ex-vivo imaging was undertaken without any support in the LV cavity, 7 animals comprised the experimental group, in which a two-step registration optimization process was undertaken. The first step involved a heart-specific flexible 3D printed scaffold generated from in-vivo CMR, which was used to maintain left ventricular (LV) shape during ex-vivo imaging. In the second step, a non-rigid co-registration algorithm was applied to align in-vivo and ex-vivo data. Tissue dimension changes between in-vivo and ex-vivo imaging were compared between the experimental and control group. In the experimental group, tissue compartment volumes and thickness were compared between in-vivo and ex-vivo data before and after non-rigid registration. The effectiveness of the alignment was assessed quantitatively using the DICE similarity coefficient.

RESULTS:

LV cavity volume changed more in the control group (ratio of cavity volume between ex-vivo and in-vivo imaging in control and experimental group 0.14 vs 0.56, p < 0.0001) and there was a significantly greater change in the short axis dimensions in the control group (ratio of short axis dimensions in control and experimental group 0.38 vs 0.79, p < 0.001). In the experimental group, prior to non-rigid co-registration the LV cavity contracted isotropically in the ex-vivo condition by less than 20% in each dimension. There was a significant proportional change in tissue thickness in the healthy myocardium (change = 29 ± 21%), but not in dense scar (change = - 2 ± 2%, p = 0.034). Following the non-rigid co-registration step of the process, the DICE similarity coefficients for the myocardium, LV cavity and scar were 0.93 (±0.02), 0.89 (±0.01) and 0.77 (±0.07) respectively and the myocardial tissue and LV cavity volumes had a ratio of 1.03 and 1.00 respectively.

CONCLUSIONS:

The pattern of the morphological changes seen between the in-vivo and the ex-vivo LV differs between scar and healthy myocardium. A 3D printed flexible scaffold based on the in-vivo shape of the LV cavity is an effective strategy to minimize morphological changes in the ex-vivo LV. The subsequent non-rigid registration step further improved the co-registration and local comparison between in-vivo and ex-vivo data.

Korea and IL, USA

Highly Sensitive and Wearable Liquid Metal-Based Pressure Sensor for Health Monitoring Applications: Integration of a 3D-Printed Microbump Array with the Microchannel. (Kim K,et al) Adv Healthc Mater. 2019 Oct 9:e1900978. doi: 10.1002/adhm.201900978.

Wearable pressure sensors capable of sensitive, precise, and continuous measurement of physiological and physical signals have great potential for the monitoring of health status and the early diagnosis of diseases. This work introduces a 3D-printed rigid microbump-integrated liquid metal-based soft pressure sensor (3D-BLiPS) for wearable and health-monitoring applications. Using a 3D-printed master mold based on multimaterial fused deposition modeling, the fabrication of a liquid metal microchannel and the integration of a rigid microbump array above the microchannel are achieved in a one-step, direct process. The microbump array enhances the sensitivity of the pressure sensor (0.158 kPa-1 ) by locally concentrating the deformation of the microchannel with negligible hysteresis and a stable signal response under cyclic loading. The 3D-BLiPS also demonstrates excellent robustness to 10 000 cycles of multidirectional stretching/bending, changes in temperature, and immersion in water. Finally, these characteristics are suitable for a wide range of applications in health monitoring systems, including a wristband for the continuous monitoring of the epidermal pulse rate for cuffless blood pressure estimation and a wireless wearable device for the monitoring of body pressure using a multiple pressure sensor array for the prevention of pressure ulcers.

AM Technologies

Livermore, CA, USA.

Scalable submicrometer additive manufacturing. (Saha SK, et al) Science. 2019 Oct 4;366(6461):105-109. doi: 10.1126/science.aax8760.

High-throughput fabrication techniques for generating arbitrarily complex three-dimensional structures with nanoscale features are desirable across a broad range of applications. Two-photon lithography (TPL)-based sub-micrometer additive manufacturing is a promising candidate to fill this gap. However, the serial point-by-point writing scheme of TPL is too slow for many applications. Attempts at parallelization either do not have submicrometer resolution or cannot pattern complex structures. We overcome these difficulties by spatially and temporally focusing an ultrafast laser to implement a projection-based layer-by-layer parallelization. This increases the throughput up to three orders of magnitude and expands the geometric design space. We demonstrate this by printing, within single-digit millisecond time scales, nanowires with widths smaller than 175 nanometers over an area one million times larger than the cross-sectional area.

Singapore

Ultrafast three-dimensional printing of optically smooth microlens arrays by oscillation assisted digital light processing.(Yuan C, et al) ACS Appl Mater Interfaces. 2019 Oct 7. doi: 10.1021/acsami.9b14692.  

Microlens array has become an important micro-optics device in various applications. Compared with traditional manufacturing approaches, DLP based printing enables fabrication of complex 3D geometries and is a possible manufacturing approach for microlens arrays. However, the nature of 3D printing objects by stacking successive 2D patterns formed by discrete pixels leads to coarse surface roughness and makes DLP based printing unsuccessful in fabricating optical components. Here, we report an oscillation assisted DLP based printing approach for fabrication of microlens arrays. Optically smooth surface (about 1 nm surface roughness) is achieved by mechanical oscillation that eliminates the jagged surface formed by discrete pixels, and a 1-3 seconds single grayscale UV exposure that removes the staircase effect. Moreover, computationally designed grayscale UV patterns allow us to fabricate microlenses with various profiles. The proposed approach paves a way to 3D print optical components with high quality, fast speed and vast flexibility.

3D Bioprinting

Brisbane, Australia

Optimization of 3D bioprinting of periodontal ligament cells. (Thattaruparambil Raveendran N, et al) Dent Mater.) 2019 Oct 7. pii: S0109-5641(19)30845-0. doi: 10.1016/j.dental.2019.08.114.  

Three-dimensional (3D) bioprinting of cells is an emerging area of research but has been not explored yet in the context of periodontal tissue engineering.

OBJECTIVE:

This study reports on the optimization of the 3D bioprinting of periodontal ligament cells for potential application in periodontal regeneration.

METHODS:

We systematically investigated the printability of various concentrations of gelatin methacryloyl (GelMA) hydrogel precursor using a micro-extrusion based three-dimensional (3D) printer. The influence of different printing parameters such as photo-initiator concentration, UV exposure, pressure and dispensing needle diameter on the viability of periodontal ligament cells encapsulated within the 3D bioprinted construct were subsequently assessed.

RESULTS:

This systematic evaluation enabled the selection of the most suited printing conditions for achieving high printing resolution, dimensional stability and cell viability for 3D bioprinting of periodontal ligament cells.

SIGNIFICANCE:

The optimized bioprinting system is the first step towards to the reproducible manufacturing of cell-laden, space maintaining scaffolds for the treatment of periodontal lesions.

Beijing, China

PCL-MECM Based Hydrogel Hybrid Scaffolds and Meniscal Fibrochondrocytes Promote Whole Meniscus Regeneration in a Rabbit Meniscectomy Model. (Chen M, et al) ACS Appl Mater Interfaces. 2019 Oct 9. doi: 10.1021/acsami.9b13611.  

Regeneration of an injured meniscus continues to be a scientific challenge, due to its poor self-healing potential. Tissue engineering provides an avenue for regenerating a severely damaged meniscus. In this study, we first investigated the superiority of five concentrations (0%, 0.5%, 1%, 2% and 4%) of meniscus extracellular matrix (MECM)-based hydrogel in promoting cell proliferation and the matrix-forming phenotype of meniscal fibrochondrocytes (MFCs). We found that the 2% group strongly enhanced chondrogenic marker mRNA expression and cell proliferation compared to the other groups. Moreover, the 2% group showed the highest glycosaminoglycan (GAG) and collagen production by day 14. We then constructed a hybrid scaffold by 3D printing a wedge-shaped poly(ɛ-caprolactone) (PCL) scaffold as a backbone, followed by injection with the optimized MECM-based hydrogel (2%), which served as a cell delivery system. The hybrid scaffold (PCL-hydrogel) clearly yielded favorable biomechanical properties close to those of the native meniscus. Finally, PCL scaffold, PCL-hydrogel, and MFCs-loaded hybrid scaffold (PCL-hydrogel-MFCs) were implanted into the knee joints of New Zealand rabbits that underwent total medial meniscectomy. Six-months post-implantation, we found that the PCL-hydrogel-MFCs group exhibited markedly better gross appearance and cartilage protection than the PCL scaffold and PCL-hydrogel groups. Moreover, the regenerated menisci in the PCL-hydrogel-MFCs group had similar histological structures, biochemical contents and biomechanical properties as the native menisci in the sham operation group. In conclusion, PCL-MECM based hydrogel hybrid scaffold seeded with MFCs can successfully promote whole meniscus regeneration, and cell-loaded PCL-MECM based hydrogel hybrid scaffold may be a promising strategy for meniscus regeneration in the future.

Hannover, Germany

Fabrication of a Monolithic Lab-on-a-Chip Platform with Integrated Hydrogel Waveguides for Chemical Sensing.(Torres-Mapa ML1, et al) Sensors (Basel). 2019 Oct 8;19(19). pii: E4333. doi: 10.3390/s19194333.

Hydrogel waveguides have found an increased use for a variety of applications where biocompatibility and flexibility are important. In this work, we demonstrate the use of polyethylene glycol diacrylate (PEGDA) waveguides to realize a monolithic lab-on-a-chip device. We performed a comprehensive study on the swelling and optical properties for different chain lengths and concentrations in order to realize an integrated biocompatible waveguide in a microfluidic device for chemical sensing. Waveguiding properties of PEGDA hydrogel were used to guide excitation light into a microfluidic channel to measure the fluorescence emission profile of rhodamine 6G as well as collect the fluorescence signal from the same device. Overall, this work shows the potential of hydrogel waveguides to facilitate delivery and collection of optical signals for potential use in wearable and implantable lab-on-a-chip devices.

Dublin Ireland

Biofabrication of multiscale bone extracellular matrix scaffolds for bone tissue engineering.

(Freeman FE, et al) Eur Cell Mater. 2019 Oct 11;38:168-187. doi: 10.22203/eCM.v038a12.

Interconnected porosity is critical to the design of regenerative scaffolds, as it permits cell migration, vascularisation and diffusion of nutrients and regulatory molecules inside the scaffold. 3D printing is a promising strategy to achieve this as it allows the control over scaffold pore size, porosity and interconnectivity. Thus, the aim of the present study was to integrate distinct biofabrication strategies to develop a multiscale porous scaffold that was not only mechanically functional at the time of implantation, but also facilitated rapid vascularisation and provided stem cells with appropriate cues to enable their differentiation into osteoblasts. To achieve this, polycaprolactone (PCL) was functionalised with decellularised bone extracellular matrix (ECM), to produce osteoinductive filaments for 3D printing. The addition of bone ECM to the PCL not only increased the mechanical properties of the resulting scaffold, but also increased cellular attachment and enhanced osteogenesis of mesenchymal stem cells (MSCs). In vivo, scaffold pore size determined the level of vascularisation, with a larger filament spacing supporting faster vessel in-growth and more new bone formation. By freeze-drying solubilised bone ECM within these 3D-printed scaffolds, it was possible to introduce a matrix network with microscale porosity that further enhanced cellular attachment in vitro and increased vessel infiltration and overall levels of new bone formation in vivo. To conclude, an “off-the-shelf” multiscale bone-ECM-derived scaffold was developed that was mechanically stable and, once implanted in vivo, will drive vascularisation and, ultimately, lead to bone regeneration.

3D Printing and Robotics

New York, USA

Robotic Surgical Assistant (ROSA™) Rehearsal: Using 3-Dimensional Printing Technology to Facilitate the Introduction of Stereotactic Robotic Neurosurgical Equipment.(Bonda DJ1, et al) Oper Neurosurg (Hagerstown). 2019 Oct 5. pii: opz281. doi: 10.1093/ons/opz281.  

BACKGROUND:

The use of frameless stereotactic robotic technology has rapidly expanded since the Food and Drug Administration’s approval of the Robotic Surgical Assistant (ROSA™) in 2012. Although the safety and accuracy of the ROSA platform has been well-established, the introduction of complex robotic technology into an existing surgical practice poses technical and logistical challenges particular to a given institution.

OBJECTIVES:

To better facilitate the integration of new surgical equipment into the armamentarium of a thriving pediatric neurosurgery practice by describing the use of a three-dimensional (3D)-printed patient model with in situ 3D-printed tumor for presurgical positioning and trajectory optimization in the stereotactic biopsy of a pontine lesion in a pediatric patient.

METHODS:

A 3D model was created with an added silicone mock tumor at the anatomical position of the lesion. In a preoperative rehearsal session, the patient model was pinned and registered using the ROSA platform, and a mock biopsy was performed targeting the in Situ silicone tumor.

RESULTS:

Utilization of the 3D-printed model enabled workflow optimization and increased staff familiarity with the logistics of the robotic technology. Biopsy trajectory successfully reached intralesional tissue on the 3D-printed model. The rehearsal maneuvers decreased operative and intubation time for the patient and improved operative staff familiarity with the robotic setup.

CONCLUSION:

Use of a 3D-printed patient model enhanced presurgical positioning and trajectory planning in the biopsy of a difficult to reach pontine lesion in a pediatric patient. The ROSA rehearsal decreased operative time and increased staff familiarity with a new complex surgical equipment.

Image Credit: Bonda DJ, et al

(About the figure above: Biopsy probe positioning on the 3D-printed patient model.)

Pontedera, Italy

Passive Morphological Adaptation for Obstacle Avoidance in a Self-Growing Robot Produced by Additive Manufacturing. (Sadeghi A1, et al.) Soft Robot. 2019 Oct 8. doi: 10.1089/soro.2019.0025.  

This article presents strategies for the passive path and morphological adaptation of a plant-inspired growing robot that can build its own body by an additive manufacturing process. By exploiting the soft state of the thermoplastic material used by the robot to build its structure, we analyzed the ability of the robot to change its direction of growth without the need for specific cognition and control processes. Obstacle avoidance is computed by the mechanics from the body-environment interaction. The robot can passively adapt its body to flat obstacles with an inclination of up to 50° with resulting reaction forces of up to ∼10 N. The robot also successfully performs penetration and body adaptation (with 30° obstacle inclination) in artificial soil and in a rough unstructured environment. This approach is founded on observing plant roots and how they move and passively adapt to obstacles in soil before they actively respond followed by cell division-based growth.

Richmond, VA, Atlanta, GA

Radiotherapy-Compatible Robotic System for Multi-Landmark Positioning in Head and Neck Cancer Treatments. (Ostyn M, et al) Sci Rep. 2019 Oct 7;9(1):14358. doi: 10.1038/s41598-019-50797-7.

The spine flexibility creates one of the most significant challenges to proper positioning in radiation therapy of head and neck cancers. Even though existing immobilization techniques can reduce the positioning uncertainty, residual errors (2-3 mm along the cervical spine) cannot be mitigated by single translation-based approaches. Here, we introduce a fully radiotherapy-compatible electro-mechanical robotic system, capable of positioning a patient’s head with submillimeter accuracy in clinically acceptable spatial constraints. Key mechanical components, designed by finite element analysis, are fabricated with 3D printing and a cyclic loading test of the printed materials captures a great mechanical robustness. Measured attenuation of most printed components is lower than analytic estimations and radiographic imaging shows no visible artifacts, implying full radio-compatibility. The new system evaluates the positioning accuracy with an anthropomorphic skeletal phantom and optical tracking system, which shows a minimal residual error (0.7 ± 0.3 mm). This device also offers an accurate assessment of the post-correction error of aligning individual regions when the head and body are individually positioned. Collectively, the radiotherapy-compatible robotic system enables multi-landmark set up to align the head and body independently and accurately for radiation treatment, which will significantly reduce the need for large margins in the lower neck.

Material Science

Shanghai, China

3D Printing of Hot Dog-Like Biomaterials with Hierarchical Architecture and Distinct Bioactivity. (Li T,et al)  Adv Sci (Weinh). 2019 Aug 8;6(19):1901146. doi: 10.1002/advs.201901146. eCollection 2019 Oct 2.

Hierarchical structure has exhibited an important influence in the fields of supercapacitors, catalytic applications, and tissue engineering. The hot dog, a popular food, is composed of bread and sausage with special structures. In this study, inspired by the structure of a hot dog, the strategy of combining direct ink writing 3D printing with bidirectional freezing is devised to prepare hot dog-like scaffolds with hierarchical structure. The scaffolds are composed of hollow bioceramic tubes (mimicking the “bread” in hot dogs, pore size: ≈1 mm) embedded by bioceramic rods (mimicking the “sausage” in hot dogs, diameter: ≈500 µm) and the sausage-like bioceramic rods possess uniformly aligned lamellar micropores (lamellar pore size: ≈30 µm). By mimicking the functions of hierarchical structure of bone tissues for transporting and storing nutrients, the prepared hot dog-like scaffolds show excellent properties for loading and releasing drugs and proteins as well as for improving the delivery and differentiation of tissue cells. The in vivo study further demonstrates that both the hierarchical structure itself and the controlled drug delivery in hot dog-like scaffolds significantly contribute to the improved bone-forming bioactivity. This study suggests that the prepared hot dog-like scaffolds are a promising biomaterial for drug delivery, tissue engineering, and regenerative medicine.

Public Health

Rehovot, Israel.

Digitizable therapeutics for decentralized mitigation of global pandemics. (Hacohen A1,2, et al) Sci Rep. 2019 Oct 4;9(1):14345. doi: 10.1038/s41598-019-50553-x.

When confronted with a globally spreading epidemic, we seek efficient strategies for drug dissemination, creating a competition between supply and demand at a global scale. Propagating along similar networks, e.g., air-transportation, the spreading dynamics of the supply vs. the demand are, however, fundamentally different, with the pathogens driven by contagion dynamics, and the drugs by commodity flow. We show that these different dynamics lead to intrinsically distinct spreading patterns: while viruses spread homogeneously across all destinations, creating a concurrent global demand, commodity flow unavoidably leads to a highly uneven spread, in which selected nodes are rapidly supplied, while the majority remains deprived. Consequently, even under ideal conditions of extreme production and shipping capacities, due to the inherent heterogeneity of network-based commodity flow, efficient mitigation becomes practically unattainable, as homogeneous demand is met by highly heterogeneous supply. Therefore, we propose here a decentralized mitigation strategy, based on local production and dissemination of therapeutics, that, in effect, bypasses the existing distribution networks. Such decentralization is enabled thanks to the recent development of digitizable therapeutics, based on, e.g., short DNA sequences or printable chemical compounds, that can be distributed as digital sequence files and synthesized on location via DNA/3D printing technology. We test our decentralized mitigation under extremely challenging conditions, such as suppressed local production rates or low therapeutic efficacy, and find that thanks to its homogeneous nature, it consistently outperforms the centralized alternative, saving many more lives with significantly less resources.

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