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.

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.

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.

The (Eigen)value of diffusion tensor imaging to investigate depression after traumatic brain injury.

BACKGROUND: Many people with a traumatic brain injury (TBI), even mild to moderate, will develop major depression (MD). Recent studies of patients with MD suggest reduced fractional anisotropy (FA) in dorsolateral prefrontal cortex (DLPFC), temporal lobe tracts, midline, and capsule regions. Some of these pathways have also been found to have reduced FA in patients with TBI. It is unknown whether the pathways implicated in MD after TBI are similar to those with MD without TBI. This study sought to investigate whether there were specific pathways unique to TBI patients who develop MD. METHODS: A sample of TBI-MD subjects (N = 14), TBI-no-MD subjects (N = 12), MD-no-TBI (N = 26), and control subjects (no TBI or MD, N = 23), using a strict measurement protocol underwent psychiatric assessments and diffusion tensor brain Magnetic Resonance Imaging (MRI). RESULTS: The findings of this study indicate that (1) TBI patients who develop MD have reduced axial diffusivity in DLPFC, corpus callosum (CC), and nucleus accumbens white matter tracts compared to TBI patients who do not develop MD and (2) MD patients without a history of TBI have reduced FA along the CC. We also found that more severe MD relates to altered radial diffusivity. CONCLUSIONS: These findings suggest that compromise to specific white matter pathways, including both axonal and myelination aspects, after a mild TBI underlie the susceptibility of these patients developing MD.

A continuous correlation between intracranial pressure and cerebral blood flow velocity reflects cerebral autoregulation impairment during intracranial pressure plateau waves.

BACKGROUND: In the healthy brain, small oscillations in intracranial pressure (ICP) occur synchronously with those in cerebral blood volume (CBV), cerebrovascular resistance, and consequently cerebral blood flow velocity (CBFV). Previous work has shown that the usual synchrony between ICP and CBFV is lost during intracranial hypertension. Moreover, a continuously computed measure of the ICP/CBFV association (Fix index) was a more sensitive predictor of outcome after traumatic brain injury (TBI) than a measure of autoregulation (Mx index). In the current study we computed Fix during ICP plateau waves, to observe its behavior during a defined period of cerebrovascular vasodilatation. METHODS: Twenty-nine recordings of arterial blood pressure (ABP), ICP, and CBFV taken during ICP plateau waves were obtained from the Addenbrooke's hospital TBI database. Raw data was filtered prior to computing Mx and Fix according to previously published methods. Analyzed data was segmented into three phases (pre, peak, and post), and a median value of each parameter was stored for analysis. RESULTS: ICP increased from a median of 22-44 mmHg before falling to 19 mmHg. Both Mx and Fix responded to the increase in ICP, with Mx trending toward +1, while Fix trended toward -1. Mx and Fix correlated significantly (Spearman's R = -0.89, p < 0.000001), however, Fix spanned a greater range than Mx. A plot of Mx and Fix against CPP showed a plateau (Mx) or trough (Fix) consistent with a zone of "optimal CPP". CONCLUSIONS: The Fix index can identify complete loss of cerebral autoregulation as the point at which the normally positive CBF/CBV correlation is reversed. Both CBF and CBV can be monitored noninvasively using near-infrared spectroscopy (NIRS), suggesting that a noninvasive method of monitoring autoregulation using only NIRS may be possible.

Assessment of cerebral autoregulation from respiratory oscillations in ventilated patients after traumatic brain injury.

Phase shift (PS) between oscillations in arterial blood pressure (ABP) and transcranial Doppler (TCD) cerebral blood flow velocity (CBFV) is thought to describe cerebral autoregulation. Ventilated patients show high amplitude and regular respiratory oscillations in ABP and CBFV, allowing reliable PS measurement. We analysed recordings of ABP, CBFV and intracranial pressure (ICP) from 187 TBI patients treated at Addenbrooke's Hospital, Cambridge, UK, from 1993 to 1998. Monitored data were recorded and PS, TCD autoregulation (Mx) and pressure reactivity (PRx) were calculated using ICM+. PS was computed by peak detection in the ABP/CBFV cross-spectrum. Recordings with low coherence (<0.5), unstable respiratory rate (RR), or PS wraparound were excluded. Median RR was 14 bpm (range 10-20 bpm). Group median PS was 13° (range -37-56°). Average PS (PSa) correlated with RR (Spearman's R = -0.302, p < 0.01, and cerebral perfusion pressure (R = -0.373, p < 0.01). Correlations of PS with Mx and PRx were weak but significant (p < 0.01). Kruskal-Wallis test for outcome vs. PS was non-significant (PSa: p = 0.14, minimum PS (PSm): p = 0.27). Mann-Whitney test for mortality vs. PS was significant (p < 0.05) for PSm only. Respiratory PS responds to changes in CPP and RR and correlates weakly with CA. Respiratory PS may have some prognostic value for patients with TBI.

Monitoring of the association between cerebral blood flow velocity and intracranial pressure.

Slow waves in intracranial pressure (ICP) are believed to originate from changes in cerebral blood volume secondary to adjustments in arteriolar diameter. Blood flow velocity (FV) signals recorded with transcranial Doppler ultrasound show similar oscillations. We investigated a continuous measure of FV/ICP association and its relationship to cerebral perfusion pressure (CPP), ICP, cerebral autoregulation (CA) and outcome after severe traumatic brain injury (TBI). We analysed recordings of arterial blood pressure (ABP), FV and ICP from 187 TBI patients treated at Addenbrooke's Hospital, Cambridge, UK, from 1993 to 1998. Monitored data were recorded and the flow-ICP index (Flx) was derived as a moving correlation between the two signals over 4-min periods using ICM+. FIx was compared with the autoregulatory index (Mx), pressure reactivity index (PRx), ICP, CPP and outcome. FIx correlated with ICP (Spearman's R = -0.40, p < 0.01), Mx (R = -0.54, p < 0.00005) and CPP (R = 0.34, p < 0.01), but not with PRx (p = 0.84). FIx was significantly associated with outcome after grouping into Glasgow Outcome Score (GOS) 1-3 or GOS 4-5 (Mann-Whitney p = 0.009). FIx may provide unique insights into the behaviour of the cerebral circulation during intracranial hypertension.

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.

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.

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.

Image guidance for rapid temporal acoustic window localisation prior to transcranial Doppler ultrasound in the neurosurgical patient.

Transcranial Doppler ultrasound (TCD) is a technically challenging procedure, when performed at the bedside in the postoperative period. Skull defects and acoustic obstacles were identified prior to TCD using 3-dimensional graphical reconstructions of patients' skulls after aneurysm surgery. We report our experiences, including a case wherein the technique facilitated completion of a successful TCD after conventional methods failed. We conclude that image guidance improves success rates, increases operator confidence and decreases procedural time for transcranial Doppler ultrasound.

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.

Slow oscillations in middle cerebral artery cerebral blood flow velocity and aging.

OBJECTIVE: A recent study using near infrared spectroscopy (NIRS) showed that low frequency oscillations of regional cerebral blood flow (CBF) decline with age. Using transcranial Doppler ultrasound (TCD), it is possible to monitor similar fluctuations in cerebral blood velocity (CBV) in basal cerebral vessels. Such oscillations have been used widely in the assessment of cerebral autoregulation. We postulated that it should be possible to observe similar age related reductions in the amplitude of slow waves recorded using TCD. METHODS: We studied 187 patients with head injury, who were admitted to Addenbrooke's Neuro Critical Care unit between 1992 and 1998. Intermittent recordings of CBV were undertaken using TCD, which were subsequently analysed using software developed in-house. Power spectra were computed in the very low frequency (VLF: 0.01-0.05 Hz) and low frequency (LF: 0.07-0.11 Hz) ranges for all signals and a regression analysis was performed to assess the correlation between power in each frequency band and age. RESULTS: No significant correlation was found between VLF or LF power and age (VLF: r=0.037; p=0.63; LF: r=-0.05, p=0.517). DISCUSSION: While remaining cogniscent of the complex nature of our patient group, we find that age dependent reductions in CBF oscillations seen using NIRS do not translate to recordings of CBV in the middle cerebral artery in patients with head injury.

Current controversies in the management of patients with severe traumatic brain injury.

BACKGROUND: Traumatic brain injury is a major cause of mortality and morbidity, particularly among young men. The efficacy and safety of most of the interventions used in the management of patients with traumatic brain injury remain unproven. Examples include the 'cerebral perfusion pressure-targeted' and 'volume-targeted' management strategies for optimizing cerebrovascular haemodynamics and specific interventions, such as hyperventilation, osmotherapy, cerebrospinal fluid drainage, barbiturates, decompressive craniectomy, therapeutic hypothermia, normobaric hyperoxia and hyperbaric oxygen therapy. METHODS: A review of the literature was performed to examine the evidence base behind each intervention. RESULTS: There is no class I evidence to support the routine use of any of the therapies examined. CONCLUSION: Well-designed, large, randomized controlled trials are needed to determine therapies that are safe and effective from those that are ineffective or harmful.