Novel Collagen Surgical Patches for Local Delivery of Multiple Drugs.

Effective control of post-operative inflammation after tissue repair remains a clinical challenge. A tissue repair patch that could appropriately integrate into the surrounding tissue and control inflammatory responses would improve tissue healing. A collagen-based hybrid tissue repair patch has been developed in this work for the local delivery of an anti-inflammatory drug. Dexamethasone (DEX) was encapsulated into PLGA microspheres and then co-electrocompacted into a collagen membrane. Using a simple process, multiple drugs can be loaded into and released from this hybrid composite material simultaneously, and the ratio between each drug is controllable. Anti-inflammatory DEX and the anti-epileptic phenytoin (PHT) were co-encapsulated and released to validate the dual drug delivery ability of this versatile composite material. Furthermore, the Young's modulus of this drug-loaded collagen patch was increased to 20 KPa using a biocompatible riboflavin (vitamin B2)-induced UV light cross-linking strategy. This versatile composite material has a wide range of potential applications which deserve exploration in further research.

Laser Sintering Approaches for Bone Tissue Engineering.

The adoption of additive manufacturing (AM) techniques into the medical space has revolutionised tissue engineering. Depending upon the tissue type, specific AM approaches are capable of closely matching the physical and biological tissue attributes, to guide tissue regeneration. For hard tissue such as bone, powder bed fusion (PBF) techniques have significant potential, as they are capable of fabricating materials that can match the mechanical requirements necessary to maintain bone functionality and support regeneration. This review focuses on the PBF techniques that utilize laser sintering for creating scaffolds for bone tissue engineering (BTE) applications. Optimal scaffold requirements are explained, ranging from material biocompatibility and bioactivity, to generating specific architectures to recapitulate the porosity, interconnectivity, and mechanical properties of native human bone. The main objective of the review is to outline the most common materials processed using PBF in the context of BTE; initially outlining the most common polymers, including polyamide, polycaprolactone, polyethylene, and polyetheretherketone. Subsequent sections investigate the use of metals and ceramics in similar systems for BTE applications. The last section explores how composite materials can be used. Within each material section, the benefits and shortcomings are outlined, including their mechanical and biological performance, as well as associated printing parameters. The framework provided can be applied to the development of new, novel materials or laser-based approaches to ultimately generate bone tissue analogues or for guiding bone regeneration.

Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.

Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma.

Cardiac Output and Cerebral Blood Flow: A Systematic Review of Cardio-Cerebral Coupling.

Control of cerebral blood flow (CBF) is crucial to the management of neurocritically ill patients. Small studies which have examined the role of cardiac output (CO) as a determinant of CBF have inconsistently demonstrated evidence of cardio-cerebral coupling. Putative physiological mechanisms underpinning such coupling include changes in arterial blood pressure pulsatility, which would produce vasodilation through increased oscillatory wall-shear-stress and baroreceptor mediated reflex sympatholysis, and changes in venous backpressure which may improve cerebral perfusion pressure. We sought to summarize and contextualize the literature on the relationship between CO and CBF and discuss the implications of cardio-cerebral coupling for neurocritical care. A systematic review of the literature yielded 41 studies; all were of low-quality and at high-risk of bias. Results were heterogenous, with evidence for both corroboration and confutation of a relationship between CO and CBF in both normal and abnormal cerebrovascular states. Common limitations of studies were lack of instantaneous CBF measures with reliance on transcranial Doppler-derived blood flow velocity as a surrogate, inability to control for fluctuations in established determinants of CBF (eg, PaCO 2 ), and direct effects on CBF by the interventions used to alter CO. Currently, the literature is insufficiently robust to confirm an independent relationship between CO and CBF. Hypothetically, the presence of cardio-cerebral coupling would have important implications for clinical practice. Manipulation of CBF could occur without the risks associated with extremes of arterial pressure, potentially improving therapy for those with cerebral ischemia of various etiologies. However, current literature is insufficiently robust to confirm an independent relationship between CO and CBF, and further studies with improved methodology are required before therapeutic interventions can be based on cardio-cerebral coupling.

Patient-specific implants for craniomaxillofacial surgery: A manufacturer's experience.

Additive manufacturing technologies have enabled the development of customised implants for craniomaxillofacial applications using biomaterials such as polymethylmethacrylate (PMMA), porous high-density polyethylene (pHDPE), and titanium mesh. This study aims to report an Australian manufacturer's experience in developing, designing and supplying patient-specific craniomaxillofacial implants over 23 years and summarise feedback received from clinicians. The authors conducted a retrospective review of the manufacturer's implant database of orders placed for custom craniomaxillofacial implants between 1996 and 2019. The variables collected included material, country of order, gender, patient age, and reported complications, which included a measure of custom implant "fit" and adverse events. The development of critical checkpoints in the custom manufacturing process that minimise clinical or logistical non-conformities is highlighted and discussed. A total of 4120 patient-specific implants were supplied, of which 2689 were manufactured from PMMA, 885 from titanium mesh, and 546 from pHDPE. The majority of the implants were used in Australia (2260), United Kingdom (412), Germany (377), and New Zealand (338). PMMA was the preferred material for cranial implants whereas pHDPE was preferred for maxillofacial applications. Age or gender did not influence the material choice. Implant "fit" and adverse outcomes were used as a metric of implant performance. Between 2007 and 2019 there were 37 infections (0.98%) and 164 non-conformities recorded of which 75 (1.8%) were related to implant 'fit'. Our experience demonstrates a safe, reliable, and clinically streamlined manufacturing process which supports surgeons that require bespoke craniomaxillofacial solutions for reconstruction surgery.

Escalating Mean Arterial Pressure in Severe Traumatic Brain Injury: A Prospective, Observational Study.

To investigate cerebral autoregulatory status in patients with severe traumatic brain injury (TBI), guidelines now suggest active manipulation of mean arterial pressure (MAP). There is a paucity of data, however, describing the effect on intracranial pressure (ICP) when MAP is raised. Consecutive patients with TBI requiring ICP monitoring were enrolled from November 2019 to April 2020. The MAP and ICP were recorded continuously, and clinical annotations were made whenever intravenous vasopressors were commenced or adjusted to defend cerebral perfusion pressure (CPP) targets. A significant change in MAP burden was defined as MAP >100min.mm Hg over 15 min. The primary outcome was the change in ICP burden over the same 15-min period. Bedside and clinical parameters were then compared between these groups. Twenty-eight patients were enrolled, providing 212 clinical events, of which 60 were deemed significant. Over the first 15 min, 65% were associated with a net negative ICP burden. A greater reduction in ICP burden was observed with events occurring in patients without a history of hypotension at scene (p = 0.016), after three days post-injury (p = 0.0018), and where the pressure-reactivity index (PRx) was <0.25 (p = 0.0005) or the ICP amplitude to CPP correlation coefficient (RAC) was <-0.10 (p = 0.0036) at the initiation of vasopressor changes. The ICP burden in the first 15 min was highly correlated with the next 15-min period. In patients with severe TBI requiring ICP monitoring, increasing MAP to pursue a CPP target was followed by a net negative ICP burden in approximately two-thirds of events. These data suggest a MAP challenge may be a useful adjunct in managing intracranial hypertension.

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 ±â€¯44 min), sterile tray usage (14 ±â€¯3), fluoroscopy screening time (57.2 ±â€¯23.7 s), operative waste (19 ±â€¯8 L contaminated, 116 ±â€¯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.

Does Exposure to Diagnostic Ultrasound Modulate Human Nerve Responses to Magnetic Stimulation?

Ultrasound (US) at diagnostic frequency and power is known to alter nerve potentials; however, the precise mechanism of action is unknown. We investigated whether US alters resting nerve potential to lower the threshold for magnetic nerve stimulation. Seventeen healthy subjects were recruited. For each subject, a 1.5 MHz US imaging probe was placed onto the elbow with the beam directed at the ulnar nerve. The probe was coupled to the skin using standard acoustic coupling gel as would be done for a routine clinical US scan. Ulnar nerve stimulation was performed simultaneously with magnetic stimulation (MS). Successful magnetic stimulation of the ulnar nerve was confirmed with nerve potentials measured by electromyography. There was no significant change in electromyography signal when MS was performed during US exposure. US at the diagnostic frequency and power tested does not alter nerve thresholds with MS. Testing at other frequencies is required, however, before US is negated as a technique to modify MS thresholds.

Advances in implantable bionic devices for blindness: a review.

Since the 1950s, vision researchers have been working towards the ambitious goal of restoring a functional level of vision to the blind via electrical stimulation of the visual pathways. Groups based in Australia, USA, Germany, France and Japan report progress in the translation of retinal visual prosthetics from the experimental to clinical domains, with two retinal visual prostheses having recently received regulatory approval for clinical use. Regulatory approval for cortical visual prostheses is yet to be obtained; however, several groups report plans to conduct clinical trials in the near future, building upon the seminal clinical studies of Brindley and Dobelle. In this review, we discuss the general principles of visual prostheses employing electrical stimulation of the visual pathways, focusing on the retina and visual cortex as the two most extensively studied stimulation sites. We also discuss the surgical and functional outcomes reported to date for retinal and cortical prostheses, concluding with a brief discussion of novel developments in this field and an outlook for the future.

Brain Neuromodulation Techniques: A Review.

The modulation of brain function via the application of weak direct current was first observed directly in the early 19th century. In the past 3 decades, transcranial magnetic stimulation and deep brain stimulation have undergone clinical translation, offering alternatives to pharmacological treatment of neurological and neuropsychiatric disorders. Further development of novel neuromodulation techniques employing ultrasound, micro-scale magnetic fields and optogenetics is being propelled by a rapidly improving understanding of the clinical and experimental applications of artificially stimulating or depressing brain activity in human health and disease. With the current rapid growth in neuromodulation technologies and applications, it is timely to review the genesis of the field and the current state of the art in this area.

The Correlation Between Intracranial Pressure and Cerebral Blood Flow Velocity During ICP Plateau Waves.

We previously showed that the flow-ICP index (Fix), a moving correlation coefficient between intracranial pressure (ICP) and cerebral blood flow velocity (CBFV), had marginally greater prognostic value for patients with traumatic brain injury (TBI) than an index of cerebral autoregulation (mean index, Mx). The aim of this study was to further examine the clinical and physiological relevance of Fix by studying its behaviour during ICP plateau waves in patients with TBI. Twenty-nine recordings of CBFV made during ICP plateau waves were analysed. Both Mx and Fix at baseline and peak ICP were significantly different, although the magnitude of Fix change was slightly greater. The correlation between Fix and cerebral perfusion pressure (CPP) was stronger than that between Mx and CPP. Unlike in our previous study, plotting Fix against CPP revealed a peak value in the range of "optimal" CPP, as indicated by the Mx versus CPP plot. The findings suggest that during periods of reduced CPP caused by plateau waves, the dynamic behaviour of Fix is similar to that of a measure of cerebral autoregulation. This conclusion needs to be verified against similar results obtained during episodes of supranormal CPP.

Electrical stimulation of the brain and the development of cortical visual prostheses: An historical perspective.

Rapid advances are occurring in neural engineering, bionics and the brain-computer interface. These milestones have been underpinned by staggering advances in micro-electronics, computing, and wireless technology in the last three decades. Several cortically-based visual prosthetic devices are currently being developed, but pioneering advances with early implants were achieved by Brindley followed by Dobelle in the 1960s and 1970s. We have reviewed these discoveries within the historical context of the medical uses of electricity including attempts to cure blindness, the discovery of the visual cortex, and opportunities for cortex stimulation experiments during neurosurgery. Further advances were made possible with improvements in electrode design, greater understanding of cortical electrophysiology and miniaturisation of electronic components. Human trials of a new generation of prototype cortical visual prostheses for the blind are imminent. This article is part of a Special Issue entitled Hold Item.

Cerebrovascular Pressure Reactivity in Children With Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury is a significant cause of morbidity and mortality in children. Cerebral autoregulation disturbance after traumatic brain injury is associated with worse outcome. Pressure reactivity is a fundamental component of cerebral autoregulation that can be estimated using the pressure-reactivity index, a correlation between slow arterial blood pressure, and intracranial pressure fluctuations. Pressure-reactivity index has shown prognostic value in adult traumatic brain injury, with one study confirming this in children. Pressure-reactivity index can identify a cerebral perfusion pressure range within which pressure reactivity is optimal. An increasing difference between optimal cerebral perfusion pressure and cerebral perfusion pressure is associated with worse outcome in adult traumatic brain injury; however, this has not been investigated in children. Our objective was to study pressure-reactivity index and optimal cerebral perfusion pressure in pediatric traumatic brain injury, including associations with outcome, age, and cerebral perfusion pressure. DESIGN: Prospective observational study. SETTING: ICU, Royal Children's Hospital, Melbourne, Australia. PATIENTS: Patients with traumatic brain injury who are 6 months to 16 years old, are admitted to the ICU, and require arterial blood pressure and intracranial pressure monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure, intracranial pressure, and end-tidal CO2 were recorded electronically until ICU discharge or monitoring cessation. Pressure-reactivity index and optimal cerebral perfusion pressure were computed according to previously published methods. Clinical data were collected from electronic medical records. Outcome was assessed 6 months post discharge using the modified Glasgow Outcome Score. Thirty-six patients were monitored, with 30 available for follow-up. Pressure-reactivity index correlated with modified Glasgow Outcome Score (Spearman ρ = 0.42; p = 0.023) and was higher in patients with unfavorable outcome (0.23 vs -0.09; p = 0.0009). A plot of pressure-reactivity index averaged within 5 mm Hg cerebral perfusion pressure bins showed a U-shape, reaffirming the concept of cerebral perfusion pressure optimization in children. Optimal cerebral perfusion pressure increased with age (ρ = 0.40; p = 0.02). Both the duration and magnitude of negative deviations in the difference between cerebral perfusion pressure and optimal cerebral perfusion pressure were associated with unfavorable outcome. CONCLUSIONS: In pediatric patients with traumatic brain injury, pressure-reactivity index has prognostic value and can identify cerebral perfusion pressure targets that may differ from treatment protocols. Our results suggest but do not confirm that cerebral perfusion pressure targeting using pressure-reactivity index as a guide may positively impact on outcome. This question should be addressed by a prospective clinical study.

A pilot study to determine whether visually evoked hemodynamic responses are preserved in children during inhalational anesthesia.

BACKGROUND: Anesthetic depth is an important parameter to monitor during surgery, yet remains difficult to quantify, particularly in young children where developmental changes influence the electroencephalogram. A more fundamental physiological response to stimulation is the increase in cerebral blood flow secondary to increased metabolic demand, referred to as flow-metabolism coupling (FMC) and measurable using near-infrared spectroscopy (NIRS). Little is known about the effect of anesthesia on FMC; therefore, we studied visually evoked hemodynamic responses (VEHRs) using NIRS in children undergoing general anesthesia for minor surgical procedures. METHOD: We recruited 23 children (aged 2-5 years), undergoing surgery requiring general anesthesia. VEHRs were measured for 30 min using NIRS, including 5 min of baseline recording after anesthetic induction. Parameters recorded using NIRS included the concentrations of oxygenated (oxy), deoxygenated (deoxy), and total hemoglobin (Hb), which were separated into epochs for evoked response analysis after filtration of motion artifact and baseline drift. Goodness-of-fit statistics and classification rules were used to determine the existence of evoked responses, and a modified Gaussian equation was used to model each evoked response. RESULTS: Near-infrared spectroscopy data were recorded in 20/23 children, of whom nine showed a VEHR. No responses were seen in the baseline control data. When examining the relationship between VEHR and anesthetic agents, we noted that for 8/10 patients in whom preoperative or intraoperative fentanyl were administered and VEHRs were absent. CONCLUSION: We have shown that VEHRs can be detected using NIRS in some anesthetized children. Administration of fentanyl was associated with an absence of VEHRs. The mechanism underlying this association is unclear.

Restoration of vision in blind individuals using bionic devices: a review with a focus on cortical visual prostheses.

The field of neurobionics offers hope to patients with sensory and motor impairment. Blindness is a common cause of major sensory loss, with an estimated 39 million people worldwide suffering from total blindness in 2010. Potential treatment options include bionic devices employing electrical stimulation of the visual pathways. Retinal stimulation can restore limited visual perception to patients with retinitis pigmentosa, however loss of retinal ganglion cells precludes this approach. The optic nerve, lateral geniculate nucleus and visual cortex provide alternative stimulation targets, with several research groups actively pursuing a cortically-based device capable of driving several hundred stimulating electrodes. While great progress has been made since the earliest works of Brindley and Dobelle in the 1960s and 1970s, significant clinical, surgical, psychophysical, neurophysiological, and engineering challenges remain to be overcome before a commercially-available cortical implant will be realized. Selection of candidate implant recipients will require assessment of their general, psychological and mental health, and likely responses to visual cortex stimulation. Implant functionality, longevity and safety may be enhanced by careful electrode insertion, optimization of electrical stimulation parameters and modification of immune responses to minimize or prevent the host response to the implanted electrodes. Psychophysical assessment will include mapping the positions of potentially several hundred phosphenes, which may require repetition if electrode performance deteriorates over time. Therefore, techniques for rapid psychophysical assessment are required, as are methods for objectively assessing the quality of life improvements obtained from the implant. These measures must take into account individual differences in image processing, phosphene distribution and rehabilitation programs that may be required to optimize implant functionality. In this review, we detail these and other challenges facing developers of cortical visual prostheses in addition to briefly outlining the epidemiology of blindness, and the history of cortical electrical stimulation in the context of visual prosthetics.

Restoration of vision using wireless cortical implants: The Monash Vision Group project.

Monash Vision Group is developing a bionic vision system based on implanting several small tiles in the V1 region of the visual cortex. This cortical approach could benefit a greater proportion of people with total blindness than other approaches, as it bypasses the eyes and optic nerve. Each tile has 43 active electrodes on its base, and a wirelessly powered electronic system to decode control signals and drive the electrodes with biphasic pulses. The tiles are fed with power and data using a common transmitting coil at the back of the patient's head. Sophisticated image processing, described in a companion paper, ensures that the user experiences maximum benefit from the small number of electrodes. This paper describes key features of this system.

Use of intracranial and ocular thermography before and after arteriovenous malformation excision.

Excision of arteriovenous malformations (AVMs) is known to carry a risk of postoperative hemorrhage, postulated to be the result of normal perfusion pressure breakthrough. It is also possible that AVMs may cause a steal effect, reducing perfusion in nearby vessels. There is currently no simple method of visualizing the presence or absence of steal effect intraoperatively. We hypothesized that the infrared thermographic (heat sensitive) imaging of perilesional brain may be useful for detecting reduced perfusion due to steal. Moreover, we hypothesized that if steal effect was present, it could impact on ocular perfusion and thereby temperature. Our objective was, therefore, to investigate whether perilesional cortical and ocular temperature (OT) may be a marker of steal effect. We intraoperatively acquired conventional and thermal images of the surgical field and eyes bilaterally, pre- and post-excisions of a large left hemisphere AVM. We found OT asymmetry preoperatively, which was absent after the AVM was excised. Intraoperative thermal images showed an increase of perilesional temperature, although this could be confounded by generalized changes in cortical perfusion due to anesthetics or surgery.

Volumetrics relate to the development of depression after traumatic brain injury.

Previous research suggests that many people who sustain a traumatic brain injury (TBI), even of the mild form, will develop major depression (MD). We previously reported white matter integrity differences between those who did and did not develop MD after mild TBI. In this current paper, we aimed to investigate whether there were also volumetric differences between these groups, as suggested by previous volumetric studies in mild TBI populations. A sample of TBI-with-MD subjects (N=14), TBI-without-MD subjects (N=12), MD-without-TBI (N=26) and control subjects (no TBI or MD, N=23), received structural MRI brain scans. T1-weighted data were analysed using the Freesurfer software package which produces automated volumetric results. The findings of this study indicate that (1) TBI patients who develop MD have reduced volume in temporal, parietal and lingual regions compared to TBI patients who do not develop MD, and (2) MD patients with a history of TBI have decreased volume in the temporal region compared to those who had MD but without a history of TBI. We also found that more severe MD in those with TBI-with-MD significantly correlated with reduced volume in anterior cingulate, temporal lobe and insula. These findings suggest that volumetric reduction to specific regions, including parietal, temporal and occipital lobes, after a mild TBI may underlie the susceptibility of these patients developing major depression, in addition to altered white matter integrity.