Paul Gamble

Bioresorbable silicon electronic sensors for the brain

Many procedures in modern clinical medicine rely on the use of electronic implants in treating conditions that range from acute coronary events to traumatic injury. However, standard permanent electronic hardware acts as a nidus for infection: bacteria form biofilms along percutaneous wires, or seed haematogenously, with the potential to migrate within the body and to provoke immune-mediated pathological tissue reactions. The associated surgical retrieval procedures, meanwhile, subject patients to the distress associated with re-operation and expose them to additional complications. Here, we report materials, device architectures, integration strategies, and in vivo demonstrations in rats of implantable, multifunctional silicon sensors for the brain, for which all of the constituent materials naturally resorb via hydrolysis and/or metabolic action, eliminating the need for extraction. Continuous monitoring of intracranial pressure and temperature illustrates functionality essential to the treatment of traumatic brain injury; the measurement performance of our resorbable devices compares favourably with that of non-resorbable clinical standards. In our experiments, insulated percutaneous wires connect to an externally mounted, miniaturized wireless potentiostat for data transmission. In a separate set-up, we connect a sensor to an implanted (but only partially resorbable) data-communication system, proving the principle that there is no need for any percutaneous wiring. The devices can be adapted to sense fluid flow, motion, pH or thermal characteristics, in formats that are compatible with the body’s abdomen and extremities, as well as the deep brain, suggesting that the sensors might meet many needs in clinical medicine.

Wireless Optofluidic Systems for Programmable In Vivo Pharmacology and Optogenetics

In vivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (μ-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens reward-related behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine.

Magnetic Resonance Imaging Biomarker of Axon Loss Reflects Cervical Spondylotic Myelopathy Severity.

Study Design. A prospective cohort study. Objective. In this study, we employed diffusion basis spectrum imaging (DBSI) to quantitatively assess axon/myelin injury, cellular inflammation, and axonal loss of cervical spondylotic myelopathy (CSM) spinal cords. Summary of Background Data. A major shortcoming in the management of CSM is the lack of an effective diagnostic approach to stratify treatments and to predict outcomes. No current clinical diagnostic imaging approach is capable of accurately reflecting underlying spinal cord pathologies. Methods. Seven patients with mild (mJOA ≥15), five patients with moderate (14≥mJOA ≥11), and two patients with severe (mJOA <11) CSM were prospectively enrolled. Given the low number of severe patients, moderate and severe patients were combined for comparison with seven age-matched controls and statistical analysis. We employed the newly developed DBSI to quantitatively measure axon and myelin injury, cellular inflammation, and axonal loss. Results. Median DBSI-inflammation volume is similar in control (266 &mgr;L) and mild CSM (171 &mgr;L) subjects, with a significant overlap of the middle 50% of observations (quartile 3 – quartile 1). This was in contrast to moderate CSM subjects that had higher DBSI-inflammation volumes (382 &mgr;L; P = 0.033). DBSI-axon volume shows a strong correlation with clinical measures (r = 0.79 and 0.87, P = 1.9 x 10–5 and 2 x 10–4 for mJOA and MDI, respectively). In addition to axon and myelin injury, our findings suggest that both inflammation and axon loss contribute to neurological impairment. Most strikingly, DBSI-derived axon volume declines as severity of impairment increases. Conclusion. DBSI-quantified axonal loss may be an imaging biomarker to predict functional recovery following decompression in CSM. Our results demonstrate an increase of about 60% in the odds of impairment relative to the control for each decrease of 100 &mgr;L in axon volume. Level of Evidence: 3

Simpson Grade I-III Resection of Spinal Atypical (World Health Organization Grade II) Meningiomas is Associated With Symptom Resolution and Low Recurrence

BACKGROUND Because of their rarity, outcomes regarding spinal atypical meningiomas (AMs) remain unclear. OBJECTIVE To describe the recurrence rate and postoperative outcomes after resection of spinal AMs, and to discuss an appropriate resection strategy and adjuvant therapy for spinal AMs. METHODS Data from all patients who presented with spinal AMs to 2 tertiary referral centers between 1998 and 2013 were obtained by chart review. RESULTS From 102 patients with spinal meningioma, 20 AM tumors (7 cervical, 11 thoracic, 2 thoracolumbar) were identified in 18 patients (median age, 50 years [range, 19-75] at time of resection; 11% male; median follow-up, 32 months [range, 1-179] after resection). Before resection, patients had sensory deficits (70%), pain (70%), weakness (60%), ataxia (50%), spasticity (65%), and incontinence (35%). One tumor presented asymptomatically. Simpson grade I, II, III, and IV resection were achieved in 3 (15%), 13 (65%), 2 (10%), and 2 (10%) tumors, respectively. One patient that underwent Simpson grade III resection received adjuvant radiation therapy. After Simpson grade I-III or gross total resection, no tumors recurred (0%; confidence interval, 0%-17.6%). After Simpson grade IV resection, 1 tumor recurred (50%; confidence interval, 1.3%-98.7%). With the exception of 1 patient who had bilateral paraplegia perioperatively, all other patients experienced improvement of preoperative symptoms after surgery (median time, 3.6 months [range, 1-13] after resection). CONCLUSION Despite published cases suggesting an aggressive clinical course for spinal AMs, this series of spinal AMs reports that gross total resection without adjuvant radiation therapy resulted in symptom resolution and low recurrence.

Serial assessment of functional recovery following nerve injury using implantable thin-film wireless nerve stimulators.

Introduction: Comprehensive assessment of the time course of functional recovery following peripheral nerve repair is critical for surgical management of peripheral nerve injuries. This study describes the design and implementation of a novel implantable wireless nerve stimulator capable of repeatedly interfacing peripheral nerve tissue and providing serial evaluation of functional recovery postoperatively. Methods: Thin‐film wireless implants were fabricated and subcutaneously implanted into Lewis rats. Wireless implants were used to serially stimulate rat sciatic nerve and assess functional recovery over 3 months following various nerve injuries. Results: Wireless stimulators demonstrated consistent performances over 3 months in vivo and successfully facilitated serial assessment of nerve and muscle function following nerve crush and nerve transection injuries. Conclusions: This study highlights the ability of implantable wireless nerve stimulators to provide a unique view into the time course of functional recovery in multiple motor targets. Muscle Nerve 54: 1114–1119, 2016

Diffusion Assessment of Cortical Changes, Induced by Traumatic Spinal Cord Injury

Promising treatments are being developed to promote functional recovery after spinal cord injury (SCI). Magnetic resonance imaging, specifically Diffusion Tensor Imaging (DTI) has been shown to non-invasively measure both axonal and myelin integrity following traumatic brain and SCI. A novel data-driven model-selection algorithm known as Diffusion Basis Spectrum Imaging (DBSI) has been proposed to more accurately delineate white matter injury. The objective of this study was to investigate whether DTI/DBSI changes that extend to level of the cerebral peduncle and internal capsule following a SCI could be correlated with clinical function. A prospective non-randomized cohort of 23 patients with chronic spinal cord injuries and 17 control subjects underwent cranial diffusion weighted imaging, followed by whole brain DTI and DBSI computations. Region-based analyses were performed on cerebral peduncle and internal capsule. Three subgroups of patients were included in the region-based analysis. Tract-Based Spatial Statistics (TBSS) was also applied to allow whole-brain white matter analysis between controls and all patients. Functional assessments were made using International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) as modified by the American Spinal Injury Association (ASIA) Scale. Whole brain white matter analysis using TBSS finds no statistical difference between controls and all patients. Only cervical ASIA A/B patients in cerebral peduncle showed differences from controls in DTI and DBSI results with region-based analysis. Cervical ASIA A/B SCI patients had higher levels of axonal injury and edema/tissue loss as measured by DBSI at the level of the cerebral peduncle. DTI Fractional Anisotropy (FA), Axial Diffusivity (AD) and Radial Diffusivity (RD) was able to detect differences in cervical ASIA A/B patients, but were non-specific to pathologies. Increased water fraction indicated by DBSI non-restricted isotropic diffusion fraction in the cerebral peduncle, explains the simultaneously increased DTI AD and DTI RD values. Our results further demonstrate the utility of DTI to detect disruption in axonal integrity in white matter, yet a clear shortcoming in differentiating true axonal injury from inflammation/tissue loss. Our results suggest a preservation of axonal integrity at the cortical level and has implications for future regenerative clinical trials.

GPR56/ADG RG1 regulates development and maintenance of peripheral myelin

Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADGRG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin—a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed “plectinopathies”—as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin.

Therapeutic electrical stimulation of injured peripheral nerve tissue using implantable thin-film wireless nerve stimulators

OBJECTIVE Electrical stimulation of peripheral nerve tissue has been shown to accelerate axonal regeneration. Yet existing methods of applying electrical stimulation to injured peripheral nerves have presented significant barriers to clinical translation. In this study, the authors examined the use of a novel implantable wireless nerve stimulator capable of simultaneously delivering therapeutic electrical stimulation of injured peripheral nerve tissue and providing postoperative serial assessment of functional recovery. METHODS Flexible wireless stimulators were fabricated and implanted into Lewis rats. Thin-film implants were used to deliver brief electrical stimulation (1 hour, 20 Hz) to sciatic nerves after nerve crush or nerve transection-and-repair injuries. RESULTS Electrical stimulation of injured nerves via implanted wireless stimulators significantly improved functional recovery. Brief electrical stimulation was observed to increase the rate of functional recovery after both nerve crush and nerve transection-and-repair injuries. Wireless stimulators successfully facilitated therapeutic stimulation of peripheral nerve tissue and serial assessment of nerve recovery. CONCLUSIONS Implantable wireless stimulators can deliver therapeutic electrical stimulation to injured peripheral nerve tissue. Implantable wireless nerve stimulators might represent a novel means of facilitating therapeutic electrical stimulation in both intraoperative and postoperative settings.

Wireless bioresorbable electronic system enables sustained nonpharmacological neuroregenerative therapy

Peripheral nerve injuries represent a significant problem in public health, constituting 2–5% of all trauma cases1. For severe nerve injuries, even advanced forms of clinical intervention often lead to incomplete and unsatisfactory motor and/or sensory function2. Numerous studies report the potential of pharmacological approaches (for example, growth factors, immunosuppressants) to accelerate and enhance nerve regeneration in rodent models3–10. Unfortunately, few have had a positive impact in clinical practice. Direct intraoperative electrical stimulation of injured nerve tissue proximal to the site of repair has been demonstrated to enhance and accelerate functional recovery11,12, suggesting a novel nonpharmacological, bioelectric form of therapy that could complement existing surgical approaches. A significant limitation of this technique is that existing protocols are constrained to intraoperative use and limited therapeutic benefits13. Herein we introduce (i) a platform for wireless, programmable electrical peripheral nerve stimulation, built with a collection of circuit elements and substrates that are entirely bioresorbable and biocompatible, and (ii) the first reported demonstration of enhanced neuroregeneration and functional recovery in rodent models as a result of multiple episodes of electrical stimulation of injured nervous tissue.A biocompatible device built from naturally dissolving components and controlled by wireless technology enables programmable electrical stimulation of injured rodent peripheral nerves to accelerate regeneration and recovery.

Bioresorbable pressure sensors protected with thermally grown silicon dioxide for the monitoring of chronic diseases and healing processes

Pressures in the intracranial, intraocular and intravascular spaces are clinically useful for the diagnosis and management of traumatic brain injury, glaucoma and hypertension, respectively. Conventional devices for measuring these pressures require surgical extraction after a relevant operational time frame. Bioresorbable sensors, by contrast, eliminate this requirement, thereby minimizing the risk of infection, decreasing the costs of care and reducing distress and pain for the patient. However, the operational lifetimes of bioresorbable pressure sensors available at present fall short of many clinical needs. Here, we present materials, device structures and fabrication procedures for bioresorbable pressure sensors with lifetimes exceeding those of previous reports by at least tenfold. We demonstrate measurement accuracies that compare favourably to those of the most sophisticated clinical standards for non-resorbable devices by monitoring intracranial pressures in rats for 25 days. Assessments of the biodistribution of the constituent materials, complete blood counts, blood chemistry and magnetic resonance imaging compatibility confirm the biodegradability and clinical utility of the device. Our findings establish routes for the design and fabrication of bioresorbable pressure monitors that meet requirements for clinical use.Bioresorbable pressure sensors with significantly improved operational lifetimes, as exemplified via the monitoring of intracranial pressure in rats for over 25 days, can be similarly accurate to analogous non-resorbable clinical devices.