Patient-specific Solutions Research Articles

3D Printing of Functionally Graded Films by Controlling Process Parameters.

Scaffolds are often used in bioengineering to replace damaged tissues. They promote cell ingrowth and provide mechanical support until cells regenerate. Such scaffolds are often made using the additive manufacturing process, given its ability to create complex shapes, affordability, and the potential for patient-specific solutions. The success of the implant is closely related to the match of the scaffold mechanical properties to those of the host tissue. Many biological tissues show properties that vary in space. Therefore, the aim is to manufacture materials with variable properties, commonly referred to as functionally graded materials. Here we present a novel technique used to manufacture porous films with functionally graded properties using 3D printers. Such an approach exploits the control of a process parameter, without any hardware modification. The mechanical properties of the manufactured films have been experimentally tested and analytically characterized.

Partial tablet coating by 3D printing.

In the last decade 3D printing (3DP) technology has gained increasing interest in the pharmaceutical field addressing several novel challenges such as on-demand manufacturing at the point of need, customization of drug release profiles and patient-specific solutions as well as combinations of several APIs in one dosage form. Therefore, 3DP can become a new and promising path to drug product development and manufacturing, able to support specific therapies and improve compliance, safety and effectiveness. The aim of this work was to partially coat tablets with a glyceride, namely Precirol ATO 5 using a semi-solids 3D printer as an approach for tuning the release of two Active Pharmaceutical Ingredients (APIs), the hydrophilic methyl-levodopa hydrochloride (Melevodopa) and the lipophilic Acyclovir. Various parameters of the 3DP coating process were purposefully modified using experimental design techniques in order to customize the selected APIs release profile, without affecting the core composition of the formulation. The percentage of the tablet surface coated, the number of coating layers as well as the coated sides of the tablet where the parameters which controlled the release profile for both APIs. Different dissolution profiles have been achieved by tuning these simple parameters, which revealed a non-Fickian release mechanism regardless of the API.

Characterization of HIV-1 diversity in various compartments at the time of primary infection by ultradeep sequencing

We used next-generation sequencing to evaluate the quantity and genetic diversity of the HIV envelope gene in various compartments in eight patients with acute infection. Plasma (PL) and seminal fluid (SF) were available for all patients, whole blood (WB) for seven, non-spermatozoid cells (NSC) for four, and saliva (SAL) for three. Median HIV-1 RNA was 6.2 log10 copies/mL [IQR: 5.5–6.95] in PL, 4.9 log10 copies/mL [IQR: 4.25–5.29] in SF, and 4.9 log10 copies/mL [IQR: 4.46–5.09] in SAL. Median HIV-1 DNA was 4.1 log10 copies/106 PBMCs [IQR: 3.15–4.15] in WB and 2.6 log10 copies /106 Cells [IQR: 2.23–2.75] in NSC. The median overall diversity per patient varied from 0.0005 to 0.0232, suggesting very low diversity, confirmed by the clonal aspect of most of the phylogenetic trees. One single haplotype was present in all compartments for five patients in the earliest stage of infection. Evidence of higher diversity was established for two patients in PL and WB, suggesting compartmentalization. Our study shows low diversity of the env gene in the first stages of infection followed by the rapid establishment of cellular reservoirs of the virus. Such clonality could be exploited in the search for early patient-specific therapeutic solutions.

Nurse Driven CVC Rounding Utilized to Improve Bone Marrow Transplant Patient Outcomes

Topic Significance & Study Purpose/Background/Rationale Central venous catheters (CVC) are frequently used in Bone Marrow Transplant (BMT) patients. BMT RNs are responsible for the care of CVC during a patient's hospitalization. CVC require dressing changes, needless connector changes, and frequent line entries. Patients with a CVC are at risk for acquiring a catheter line associated bloodstream infection (CLABSI). Due to BMT patients having compromised immune systems and altered gut integrity, the risk for acquiring a CLABSI is exponentially higher. Methods, Intervention, & Analysis A nurse led BMT unit based team was formed which became known as BMT CVC Representatives. CVC Representatives function as resources for team members, patients, and families. A CVC Representative rounds weekly on all patients on the BMT unit. Along with assessing the status of CVC dressings, activities include monitoring chlorhexidine (CHG) bathing (including education on CHG bathing to team members, patients, and families), monitoring passive disinfection devices, identifying patients with potential for CLABSI and assisting in crafting interventions for CLABSI prevention, mitigating potential CVC complications, and participating in CLABSI huddles. Findings & Interpretation BMT CVC Representatives are able to foster frontline engagement and identification of interventions that align with the goal to delivering exceptional and safe care. The interventions practiced at the bedside are critical to the patients' overall health and achievement of quality outcomes. The team is able to collaborate in mitigating patient specific solutions when dealing with challenging CVC care situations. BMT CLABSI infection rate continues to be a focus with the CLABSI rate at 2.00 BSI per 1,000 catheter line days at the end of fiscal year 2019 as compared to 2.65 BSI per 1,000 catheter line days at the end of fiscal year 2018. Discussion & Implications There has been an increase in awareness of CVC care which directly effects the BMT patient's health and outcomes. With weekly rounds the BMT CVC Representatives are able to be a resource for the team, patients, and families. They are a constant advocate for CHG bathing and other CLABSI prevention interventions.

Measuring the performance of patient-specific solutions for minimally invasive transforaminal lumbar interbody fusion surgery

Pre-surgical planning using 3D-printed BioModels enables the preparation of a “patient-specific” kit to assist instrumented spinal fusion surgery. This approach has the potential to decrease operating time while also offering logistical benefits and cost savings for healthcare. We report our experience with this method in 129 consecutive patients undergoing minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) over 27 months at a single centre and performed by a single surgeon. Patient imaging and surgical planning software were used to manufacture a 3D-printed patient-specific MIS TLIF kit for each patient consisting of a 1:1 scale spine BioModel, stereotactic K-wire guide, osteotomy guide, and retractors. Pre-selected pedicle screws, rods, and cages were sourced and supplied with the patient-specific kit. Additional implants were available on-shelf to address a size discrepancy between the kit implant and intraoperative measurements. Each BioModel was used pre-operatively for surgical planning, patient consent and education. The BioModel was sterilised for intraoperative reference and navigation purposes. Efficiency measures included operating time (153 ± 44 min), sterile tray usage (14 ± 3), fluoroscopy screening time (57.2 ± 23.7 s), operative waste (19 ± 8 L contaminated, 116 ± 30 L uncontaminated), and median hospital stay (4 days). The pre-selected kit implants exactly matched intraoperative measurements for 597/639 pedicle screws, 249/258 rods, and 46/148 cages. Pedicle screw placement accuracy was 97.8% (625/639) on postoperative CT. Complications included one intraoperative dural tear, no blood products administered, and six reoperations. Our experience demonstrates a viable application of patient-specific 3D-printed solutions and provides a benchmark for studies of efficiency in spinal fusion surgery.

Multi-level customized 3D printing for autogenous implants in skull tissue engineering

Three-dimensional (3D) printing of decellularized extracellular matrix (ECM) has been achieved to ensure real physiological environments for tissue engineering. However, the limited source, biocompatibility, and biosafety of decellularized ECM are deficiencies in its large clinical use. Autogenous ECM is biocompatible, bioactive, and biosafe, making it an optimal choice for future clinical applications of 3D printing. Here, we developed a multi-level customized 3D printing (MLC-3DP) strategy applying autogenous bone matrix (Auto-BM). This MLC-3DP includes shape specificity (shape), material specificity (Auto-BM), and cell specificity (autogenous cells) for true patient-specific repairs. Auto-BM (skull flaps) is readily accessible for specific patients after craniectomy, providing sufficient autogenous materials for MLC-3DP. Under mild conditions of this strategy, human-scale 3D printed samples can be fabricated using bioactive micron-sized Auto-BM particles. Multi-level customized autogenous bones (MLC-Auto-Bones) are finally obtained by combining autogenous bone marrow-derived mesenchymal stem cells (Auto-BMSCs). With autogenous materials and cells, MLC-Auto-Bones are inherently biocompatible and biosafe, providing good bioactivity for osteogenesis. In this implant, Auto-BMSCs can spontaneously differentiate into osteoblasts in vitro without additional osteogenic factors. In critical-sized skull defect models in vivo (3 months), implants integrate tightly to the defects’ margin, facilitate mineralization, and generate vascularized mature bone. This work provides not only feasibility for patient-specific implants for skull defects, but also potential patient-specific solutions for other similar clinical requirements.

Current Strategies in Post-traumatic Orbital Reconstruction.

Posttraumatic orbital reconstruction is one of the most fascinating fields in reconstructive craniomaxillofacial surgery. Hardly any other field in craniomaxillofacial surgery has changed so much in terms of diagnostics, biomaterial selection for reconstruction, surgical techniques including approaches and quality control. In particular, in the field of reconstructive orbital surgery all advances in modern medical treatment are summarized and represented. Reconstructive orbital surgery thus became the medical field spearheading all reconstructive surgical specialties in terms of use of DICOM-data, computer assistance, change towards patient-specific solutions and establishing digital workflows for adequate quality control during all phases of treatment, i.e. pre-, intra- and postoperative. With this paper, this evolutionary process shall be demonstrated as well as display the spirit of change that was necessary to optimize reconstructive orbital surgery and to improve medical care in all areas of reconstruction. Finally, reconstructive orbital surgery could prove to be a highly foreseeable field nowadays, thus giving the next generation of CMF-surgeons a huge opportunity to drive this topic further into the future.

Effect of Different Porosity Ratio on Mechanical Properties of Polycaprolactone and Polylactic Acid Scaffolds

In recent years, patient-specific solutions and additive manufacturing (AM) have become increasingly important in the treatment of bone defects in studies performed on the medical field. In this direction, additive manufacturing methods use in scaffold fabrication, and many advantages of these systems come to the forefront. Porosity affects the mechanical properties, biocompatibility, and biodegradability of tissue engineering scaffolds. In this study, the effect of different porosity ratios on the mechanical properties of scaffolds for polylactic acid (PLA) and polycaprolactone (PCL) scaffolds was studied. With this fabrication method can be formed entirely 3D interconnected porous scaffolds with pore size. Three different (20%, 35%, and 50%) porosity ratios were determined for both materials, and the mechanical properties of the samples were determined by compression test. The scaffolds fabricated with larger pore size showed lower mechanical performance compared to scaffolds with smaller pore size.

Designing patient-specific 3D printed devices for posterior atlantoaxial transarticular fixation surgery

Atlantoaxial transarticular screw fixation is an effective technique for arthrodesis. Surgical accuracy is critical due to the unique anatomy of the atlantoaxial region. Intraoperative aids such as computer-assisted navigation and drilling templates offer trajectory guidance but do not eliminate screw malposition. This study reports the operative and clinical performance of a novel process utilising biomodelling and 3D printing to develop patient specific solutions for posterior transarticular atlantoaxial fixation surgery. Software models and 3D printed 1:1 scale biomodels of the patient's bony atlantoaxial spine were developed from computed tomography data for surgical planning. The surgeon collaborated with a local medical device manufacturer using AnatomicsC3D to design patient specific titanium posterior atlantoaxial fixation implants using transarticular and posterior C1 arch screws. Software enabled the surgeon to specify screw trajectories, screw sizes, and simulate corrected atlantoaxial alignment allowing patient specific stereotactic drill guides and titanium posterior fixation implants to be manufactured using 3D printing. Three female patients with unilateral atlantoaxial osteoarthritis were treated using patient specific implants. Transarticular screws were placed using a percutaneous technique with fluoroscopy and neural monitoring. No screw malposition and no neural or vascular injuries were observed. Average operating and fluoroscopy times were 126.0 ± 4.1 min and 36.7 ± 11.5 s respectively. Blood loss was <50 ml per patient and length of stay was 4–6 days. Clinical and radiographic follow up data indicate satisfactory outcomes in all patients. This study demonstrates a safe, accurate, efficient, and relatively inexpensive process to stabilise the atlantoaxial spine using transarticular screws.

3D Printing of Photocurable Cellulose Nanocrystal Composite for Fabrication of Complex Architectures via Stereolithography.

The advantages of 3D printing on cost, speed, accuracy, and flexibility have attracted several new applications in various industries especially in the field of medicine where customized solutions are highly demanded. Although this modern fabrication technique offers several benefits, it also poses critical challenges in materials development suitable for industry use. Proliferation of polymers in biomedical application has been severely limited by their inherently weak mechanical properties despite their other excellent attributes. Earlier works on 3D printing of polymers focus mainly on biocompatibility and cellular viability and lack a close attention to produce robust specimens. Prized for superior mechanical strength and inherent stiffness, cellulose nanocrystal (CNC) from abaca plant is incorporated to provide the necessary toughness for 3D printable biopolymer. Hence, this work demonstrates 3D printing of CNC-filled biomaterial with significant improvement in mechanical and surface properties. These findings may potentially pave the way for an alternative option in providing innovative and cost-effective patient-specific solutions to various fields in medical industry. To the best of our knowledge, this work presents the first successful demonstration of 3D printing of CNC nanocomposite hydrogel via stereolithography (SL) forming a complex architecture with enhanced material properties potentially suited for tissue engineering.

The role of impairment of mesenchymal stem cell function in osteoporotic bone fracture healing.

With demographic change and increasing life expectancy, osteoporotic fractures have become one of the most prevalent trauma conditions seen in daily clinical practice. A variety of factors are known to affect the rate of healing in osteoporotic conditions (e.g. both biochemical and biomechanical environment of callus cells). However, the influence of impairment of mesenchymal stem cell function in the osteoporotic condition on bone fracture healing has not been fully understood. In the present study, we develop a mathematical model that quantifies the change in biological processes within the fracture callus as a result of osteoporosis. The model includes special features of osteoporosis such as reduction in mesenchymal stem cell (MSC) number in osteoporotic bone, impaired response of osteoporotic MSCs to their biomechanical microenvironment and the effects of configuration of locking compression plate (LCP) system on healing in this context. The results presented here suggest that mechanically-mediatedMSCs differentiation at early stages of healing are significantly affected under osteoporotic conditions, while it is predicted that the flexible fixation achieved by increasing bone-plate distance of LCP could alleviate the negative effects of osteoporosis on healing. The outcomes of this study could potentially lead to patient specific surgical solutions, and thus achieve optimal healing outcomes in osteoporotic conditions.

The elective management of maxillofacial trauma: improving surgical outcomes using computer-aided design and rapid prototyping for patient-specific solutions

The elective management of maxillofacial trauma: improving surgical outcomes using computer-aided design and rapid prototyping for patient-specific solutions

3D-Printing Technologies for Craniofacial Rehabilitation, Reconstruction, and Regeneration.

The treatment of craniofacial defects can present many challenges due to the variety of tissue-specific requirements and the complexity of anatomical structures in that region. 3D-printing technologies provide clinicians, engineers and scientists with the ability to create patient-specific solutions for craniofacial defects. Currently, there are three key strategies that utilize these technologies to restore both appearance and function to patients: rehabilitation, reconstruction and regeneration. In rehabilitation, 3D-printing can be used to create prostheses to replace or cover damaged tissues. Reconstruction, through plastic surgery, can also leverage 3D-printing technologies to create custom cutting guides, fixation devices, practice models and implanted medical devices to improve patient outcomes. Regeneration of tissue attempts to replace defects with biological materials. 3D-printing can be used to create either scaffolds or living, cellular constructs to signal tissue-forming cells to regenerate defect regions. By integrating these three approaches, 3D-printing technologies afford the opportunity to develop personalized treatment plans and design-driven manufacturing solutions to improve aesthetic and functional outcomes for patients with craniofacial defects.

Accuracy of an adjustable patient-specific guide for acetabular alignment in hip replacement surgery (Optihip).

Implant malalignment in hip arthroplasty increases the risk of revision surgery due to problems such as hip instability, wear, and impingement. Traditional instrumentation lacks accuracy and does not individualize the goal. Computer-assisted surgery (CAS) and patient-specific solutions improve accuracy but add considerably to the cost, amongst other drawbacks. We developed an adjustable mechanical device, called Optihip, which is set to a patient-specific goal preoperatively and is independent of pelvis position intraoperatively. The purpose of the present study was to evaluate Optihip's accuracy ex vivo. Acetabular components were implanted into six cadaveric specimens, 12 hips, by two surgeons, with the device individually adjusted according to preoperative templating on computed tomography (CT) images relative to defined acetabular rim landmarks; options also exist for templating on single or biplanar X-rays. Intraoperatively, the device was positioned on the corresponding anatomical landmarks allowing the insertion of a guide pin, which then defined the desired orientation of the acetabular cup during impaction. Mean absolute difference between the preoperatively planned cup alignment and final acetabular cup orientation, measured from postoperative CT images, was 2.5±1.2° for inclination and 2.5±2.2° for version with maximum values of 4.7° and 6.8°, respectively. Compared with previous in vivo reports, Optihip guided the acetabular cup orientation more accurately than conventional hip arthroplasty, and comparably to CAS or patient-specific systems, while fitting into the normal surgical workflow. Although clinical testing is required to confirm these experimental results, the positive ex vivo accuracy suggests good potential for improving revision rates and patient functional outcome.

Molecular Insights Provide the Critical Path to Disease Mitigation

The revolution in scientific innovation, driven by the engines of enabling technologies, is increasingly capable of deconstructing complex disease processes for the express purpose of reconstructing patient-specific solutions. These revelations in biological mechanisms provide the pressure points of opportunity for radical discovery and development to advance modern health care. Principles of mechanism-based discovery and their translation into therapeutic algorithms will, however, be challenged in the near term by emerging global public health crises that currently have no immediate solutions: chronic diseases, obesity, antibiotic-resistant infections, dementia, depression. The threat of these pandemics (multiplied in an increasingly aging population), the global burden of disease they represent, and their worldwide assault on human capital underscore the importance of continued and accelerated investments in science-propelled practice advancement, converting new knowledge into delivery of tangible health solutions. In that context, this annual issue of CPT on therapeutics innovations highlights remarkable recent successes in the discovery-development paradigm translating molecular innovations into diagnostic and therapeutic realities that transform the management of disease, impacting global health.

First pilot trial of the STAR-Liege protocol for tight glycemic control in critically ill patients

Tight glycemic control (TGC) has shown benefits in ICU patients, but been difficult to achieve consistently due to inter- and intra- patient variability that requires more adaptive, patient-specific solutions. STAR (Stochastic TARgeted) is a flexible model-based TGC framework accounting for patient variability with a stochastically derived maximum 5% risk of blood glucose (BG) below 72mg/dL. This research describes the first clinical pilot trial of the STAR approach and the post-trial analysis of the models and methods that underpin the protocol.The STAR framework works with clinically specified targets and intervention guidelines. The clinically specified glycemic target was 125mg/dL. Each trial was 24h with BG measured 1–2hourly. Two-hourly measurement was used when BG was between 110–135mg/dL for 3h. In the STAR approach, each intervention leads to a predicted BG level and outcome range (5–95th percentile) based on a stochastic model of metabolic patient variability. Carbohydrate intake (all sources) was monitored, but not changed from clinical settings except to prevent BG<100mg/dL when no insulin was given. Insulin infusion rates were limited (6U/h maximum), with limited increases based on current infusion rate (0.5–2.0U/h), making this use of the STAR framework an insulin-only TGC approach. Approval was granted by the Ethics Committee of the Medical Faculty of the University of Liege (Liege, Belgium).Nine patient trials were undertaken after obtaining informed consent. There were 205 measurements over all 9 trials. Median [IQR] per-patient results were: BG: 138.5 [130.6–146.0]mg/dL; carbohydrate administered: 2–11g/h; median insulin:1.3 [0.9–2.4]U/h with a maximum of 6.0 [4.7–6.0]U/h. Median [IQR] time in the desired 110–140mg/dL band was: 50.0 [31.2–54.2]%. Median model prediction errors ranged: 10–18%, with larger errors due to small meals and other clinical events. The minimum BG was 63mg/dL and no other measurement was below 72mg/dL, so only 1 measurement (0.5%) was below the 5% guaranteed minimum risk level.Post-trial analysis showed that patients were more variable than predicted by the stochastic model used for control, resulting in some of the prediction errors seen. Analysis and (validated) virtual trial re-simulating the clinical trial using stochastic models relevant to the patient's particular day of ICU stay were seen to be more accurate in capturing the observed variability. This analysis indicated that equivalent control and safety could be obtained with similar or lower glycemic variability in control using more specific stochastic models.STAR effectively controlled all patients to target. Observed patient variability in response to insulin and thus prediction errors were higher than expected, likely due to the recent insult of cardiac surgery or a major cardiac event, and their immediate recovery. STAR effectively managed this variability with no hypoglycemia. Improved stochastic models will be used to prospectively test these outcomes in further ongoing clinical pilot trials in this and other units.

Optimal positive end-expiratory pressure in mechanically ventilated patients: a clinical study

The optimal level of positive end-expiratory pressure (PEEP) is still widely debated in treating acute respiratory distress syndrome (ARDS) patients. Current methods of selecting PEEP only provide a range of values and do not provide unique patient-specific solutions. Model-based methods offer a novel way of using non-invasive pressure-volume (PV) measurements to estimate patient recruitability. This paper examines the clinical viability of such models in pilot clinical trials to assist therapy, optimise patient-specific PEEP, and assess the disease state and response over time.

Microsurgical Reconstruction of the Jaw With Fibular Grafts and Implants

Reconstructive treatments for jaw defects are complex procedures that can combine multiple techniques including fibula free flap (FFF) grafting. The purpose of this retrospective study was to document and share our experience on mandibular and maxillar reconstruction with FFF followed by secondary dental rehabilitation using implant insertion.We reviewed 198 patients treated by FFF grafting for mandibular and/or maxillary defects in our department during the past 11 years (1996-2007). A selection of 30 patients (18 males and 12 females, mean age of 46 y) with adequate criteria (hygiene, motivation, and prognosis) received secondary placement of osseointegrated implants. The implant success was clinically and radiographically evaluated.A total of 105 osseointegrated implants were placed in the grafted fibulas 5 months to 3 years after the reconstruction surgery. Only 4 implants were lost because of peri-implantitis (3 patients) and fibular fracture (1 patient); this corresponds to a 96.2% implant success rate.During the mean follow-up of 76 months, patient's satisfaction and functional and aesthetic results were evaluated. Radiologic findings indicated a low crest resorption around the implants despite an unfavorable crown-to-root ratio.The main difficulties in the reconstructions were lack of FFF height, absence of a vestibular groove, limitation of mouth opening, skin paddle thickness, and the reconstruction of surrounding tissues including the lip. Our management strategy is discussed.Prosthetic choice is fundamental to achieving patient-specific solutions. The prostheses used included sealed or screwed bridge, resin-bonded bridge, tooled bar, implant-borne denture, or implant-stabilized dentures. Dental implants may be used even in situations involving an unfavorable crown-to-root ratio and implant position by using milled bar and overdenture. The FFF provides a consistent bone graft that allows a reliable and predictable restoration with dental implants, leading to a satisfactory functional and aesthetic restoration.

Toward a VPH/Physiome ToolKit

The Physiome Project was officially launched in 1997 and has since brought together teams from around the world to work on the development of a computational framework for the modeling of the human body. At the European level, this effort is focused around patient-specific solutions and is known as the Virtual Physiological Human (VPH) Initiative.Such modeling is both multiscale (in space and time) and multiphysics. This, therefore, requires careful interaction and collaboration between the teams involved in the VPH/Physiome effort, if we are to produce computer models that are not only quantitative, but also integrative and predictive.In that context, several technologies and solutions are already available, developed both by groups involved in the VPH/Physiome effort, and by others. They address areas such as data handling/fusion, markup languages, model repositories, ontologies, tools (for simulation, imaging, data fitting, etc.), as well as grid, middleware, and workflow.Here, we provide an overview of resources that should be considered for inclusion in the VPH/Physiome ToolKit (i.e., the set of tools that addresses the needs and requirements of the Physiome Project and VPH Initiative) and discuss some of the challenges that we are still facing.