Mario I Romero-Ortega - US grants

DESCRIPTION (provided by applicant): Several simple hollow tubes made of biosynthetic materials (i.e.,) polylactic-co-e-coprolactone, polyglycolide, collagen) are currently FDA-approved and have demonstrated clinical benefit in the repair of short nerve gaps. However, autografts remain the treatment of choice for nerve defects despite the need of donor nerve harvest and the associated morbidity of this procedure. In contrast to short gap injuries, autografts achieve minimal functional recovery for nerve defects longer than 30 mm and simple tubularization methods fail completely in repairing this critical gap. The regenerative failure of peripheral nerves through long-gaps seems to be due at least in part, to the lack of appropriate growth substrate and trophic support. We hypothesize that a growth factor strategy targeted to a broad cellular base in the regenerating nerves would be highly effective in achieving simultaneous cellularization, vascularization and nerve regeneration through long nerve gaps. A systematic evaluation of the trophic support needed for long-gap nerve repair, as well as the combination of increased regenerative area and pleiotrophic growth factor support is lacking. This study will address this need. In our preliminary studies, we have demonstrated that multiluminal nerve repair and pleiotrophic growth factors can successfully mediate nerve regeneration across a 30 mm gap. The overall goal of the proposed study will be focused on extending these results and systematically test the effect of neurotrophic factors (i.e., NGF and NT-3) alone or combined with PTN in long gap nerve repair. In Specific Aim 1 we will test the regenerative potency of combined Neurotrophin-Pleiotrophin treatment in vitro. In Specific Aim 2 we will evaluate the effect of neurotrophin/pleiotrophic growth factor support over long-gap nerve regeneration of the rabbit common personal nerve. This study is novel in that: 1) utilizes multicellular growth factors to stimulate both glial cellular proliferation and migration, and axonal regeneration, 2) uses collagen-suspended polymeric microparticles with encapsulated growth factors for controlled release, and 3) utilizes a recently developed multiluminal hydrogel nerve scaffold as biomimetic structural support. This research will contribute towards the elucidation of the structural and trophic support required to repair long gap nerve injuries trough biosynthetic nerve implants. PUBLIC HEALTH RELEVANCE: Implantable biosynthetic nerves are promising alternatives to autogenic nerve grafting, the standard of care for gap nerve injuries, due to their ability to mediate functional recovery without the need of sacrificing donor nerves or bearing the risk associated with tissue harvest morbidity. However, repairing critical gaps longer than 30 mm remains a formidable challenge. This research will contribute towards the elucidation of the structural and trophic support required to repair long gap nerve injuries trough biosynthetic nerve implants.

Proposal #: 13-38118 Collaborative Proposal #: 13-37866
PI(s): Makedon, Fillia S PI(s): Betke, Margrit
Athitsos, Vassilis; Gatchel, Robert J; Huang, Heng; Romero-Ortega, Mario I
Institution: University of Texas-Arlington INstitution: Boston Univeristy
Title: MRI/Dev :Collab Dev. of iRehab, an Intelligent Closed-loop Instrument for Adaptive Rehabilitation
Project Proposed:
This project, developing of an instrument referred to as iRehab, aims to enable personalized rehabilitation therapy for individuals suffering from brain injury, motor disabilities, cognitive impairments, and/or psychosocial symptoms. The instrument, a modular rehabilitation device, in its simplest form consists of a computer, a camera, and adaptive software for assessment and training of cognitive functions. In its final, most complex form, the instrument will integrate data from a 4-degree-of-freedom robotic-arm with gimbals and torque sensing, a Kinect sensor, multiple cameras, an eye-tracking device, a touch screen, a microphone, and an fNIRS brain imaging sensor.
The instrument will be developed in two phases. In the first phase, the investigators develop a Barrett robot arm. In the second phase, the instrument will extend to a Kinect sensor, multiple cameras, an eye-tracking device, and related low-cost components, along with the assessment software for assessing motor function and cognitive, emotional, and personality functioning.
iRehab consists integrates multidisciplinary methodologies and sensors to assess and assist the cognitive and physical rehabilitation of persons affected by various impairments. This work highly interdisciplinary work follows a cyber-physical approach. It provides new research opportunities across the fields of human-centered computing, computer vision, assistive technology, robotics, machine learning, and neuroimaging. This work advances research in human brain activity mapping, personalized medicine, and big data.
Broader Impacts:
The proposed instrument exhibits potential for large broader impact as it directly contributes to future healthcare and human wellbeing improving accessibility to affordable rehabilitation for a broad range of patients. The instrument is likely to accelerate the recovery of a large spectrum of injuries and diseases including those causing motor, neurological, and cognitive disorders. An education plan includes course development, internships, workshops and tutorials, and an on-line resource center. In addition to many educational impacts, impact will be felt on the fundamental research in the areas addressed.

Summary Over 1.7 million people suffer from limb loss in the United States and this number is estimated to increase by 185,000 per year for upper extremity loss. Robotic limbs are highly sophisticated, achieving similar movements compared to the human counterparts, can contain sensors that measure direction and speed of motion, and can be covered with advanced synthetic electronic skin that can detect changes in temperature, humidity, and pressure. Amputees can control their prosthetic limbs by implanted electrodes in their premotor cortex or in the peripheral nerves that can detect volitional intent and translate it into movement of the robotic limb. However, evoking a naturalistic sensation from the engineered sensors in the bionic limb remains a formidable challenge. A fundamental limitation lies in the fact that such signals are conveyed to the user through electrical stimulation of the peripheral nerves, which contain a mixed modality of motor and sensory populations, many of which are indiscriminately depolarized during electrical stimulation, thus producing abnormal tingling, buzzing or burning sensation. Specific sensory modality percepts such as proprioception, mechanoception, nociception or thermoception cannot be reproducibly elicited. Thus, despite much progress in electronic skin sensors and robotic prosthetic devices, this information cannot be naturistically conveyed to the users. This limitation is critical as it obligates users to rely on visual feedback to move and position their prosthetic limbs; such cognitive burden discourages the use of advanced robotic prosthesis. Therefore, there is a need to develop closed-looped interfaces that incorporate somatosensory information vital for achieving stable and adaptive motor control, particularly for grasp and manipulation tasks where visual feedback alone is insufficient. The goal of this study is to develop modality-defined neural interfaces capable of specifically recording from motor neurons and stimulating modality-specific sensory neurons with high selectivity and stability. We aim to 1) define the selectivity and potency of neuron- and glial-derived growth factors for in vivo chemotaxis of motor and sensory neurons; 2) to evaluate the degree by which axon type submodalities can be segregated from a regenerating mixed population nerve using competitive attractants; and 3) to decode movement intent, and evoke modality-specific sensation via molecularly guided neural interfacing.

Romero-Ortega+ ! Summary Pelvic floor muscles (PFM) form a dome-shaped muscle complex are critical in urinary continence, defecation and sexual functions, and weakening pelvic floor muscles can cause uncontrolled detrusor activity, urgency, and urinary incontinence (UI), a condition that affects 30-60% of women in the US. Recently, there is an increasing appreciation for the importance of the specific pattern of activity of antagonistic muscles in the pelvic floor, and a realization that dysfunctional timing, reduced amplitude or disorganized pattern of activity in individual muscles, critically impact their ability to maintain the urethra closed, resulting in urine leakage. Here, we hypothesize that selective and coordinated stimulation of individual PFM nerves will re-establish their normal strength and activity patterns, effectively reversing the symptoms of UI. To that end, we have established a rabbit model of UI that replicates several aspects of the human condition, including the specific pattern of activation of individual levator ani and perineal muscles during the storage and voiding phases. This proposal is innovative in that it uses a state-of-the-art miniaturized wireless electrodes to enable the interfacing of small PFM efferent nerves and directly modulate their individual activity. Our preliminary studies show that compromised micturition resulting from altered PFMs activity caused by multi-parity or aging in rabbits, can be reversed using selective PFM neuromodulation (SPNM). We specifically seek to: 1) define the activation parameters for maximal muscle force and limited fatigue for individual PFM, 2) evaluate the efficacy of patterned PFM activity by SPNM in young multiparous and aging multiparous animals, and 3) demonstrate that chronic electrical stimulation of PFM nerves can improved UI symptoms long-term, and test if that SPNM benefit persists after discontinuing the neuromodulation treatment. This proposal will provide new information on the physiological role of the PFM in urinary function, and will evaluate the selective neuromodulation of these muscles as a potential therapy for drug resistant UI.

Project Summary Approximately 4 million amputees globally, a number estimated to grow 200,000 annually. Upper limb amputees traditionally use passive, body powered, or electrically powered prostheses that use surface Electromyographic (EMG) signals from intact muscles in the residual limb for movement, despite the motion artifacts, variability and need of visual and/or surrogate sensory control by the user. Advanced peripheral nervous system (PNS) interfaces have been proposed as a viable mechanism to improve the control by amputees, by reading naturalistic sensory feedback from the robotic prosthetics. Unfortunately, current neural interfaces suffer from common challenges, and electrode failure, signal deterioration over time, EMG contamination and electrical and unstable sensory percepts, including ?stings or tingles? remain a challenge. This study is uses two novel strategies designed to increase the selectivity of recording/stimulation at the PNS interface: 1) The use of an innovative regenerative multi-electrode interface with ultra-small recording sites using our recently developed ultra-thin multielectrode array , and 2) incorporation of molecular guidance cues to influence the type of sensory neurons at the neural interface. This selectivity Regenerative Ultramicro Multielectrode Array (RUMEA) is designed to discriminate between motor and cutaneous neural interfacing by combining it with molecular guidance to biologically engineer the content of sensory-motor axons at the electrode interface. Three specific aims are included: In SA1 36-electrode RUMAs, straight and Y-shape devices, will be fabricated and electrochemical and mechanical tested. In SA2 we seek to demonstrate selective recording from motor axons and evoke touch percepts using the RUMA. In SA3, we will demonstrate selective interfacing of motor and tactile axons in an upper limb amputee rat model of bidirectional Nerve Machine Interface using molecularly guided RUMAs. If successful, this strategy will demonstrate the benefit for using RUMA for selective recording from motor axons, and stimulation of sensory modality axons that evoke naturalistic sensory percepts. This advancement in peripheral neural interfaces for amputees, will reduce the cognitive burden for users of robotic prosthetics, and decrease the abnormal sensations associated with electrical stimulation in the PNS.