Shriya S. Srinivasan

Recent advances in the development of in-body bioelectronic systems are providing new opportunities for the clinical management of various diseases and disorders. These emerging technologies are tailored to specific organs and are beginning to blend both diagnostic sensing and therapeutic actuation. The aim of these systems is to seamlessly integrate with the physiological environment, as illustrated by the diverse device strategies discussed throughout this article. Next generation modalities, such as optogenetics combining gene therapy with devices for photostimulation, are gaining popularity and offer advantages over existing therapeutic strategies. In this perspective, we explore the current state of technological developments, key challenges in the field and potential pathways for translating these innovations into clinical practice.

Peripheral nerve injuries lead to diminished function and pain via nociplastic phenomena. We propose a new strategy called directed functional reinnervation, in which nerves are reassigned to new peripheral targets with the intention of altering circuit function. Here, we redirect the saphenous sensory nerve into a skeletal muscle graft to curb nociplasticity and provide benign sensations or useful inputs for prosthetic applications. Electrophysiological functional characterization demonstrated robust afferent responses to mechanical stimulation of the muscle. Immunofluorescence staining indicated widespread innervation of various synapses within the muscle graft. With immediate graft placement, the injured nerve's dorsal root ganglia revealed comparable levels of nociceptive markers to uninjured nerves, suggesting a molecular basis for the prevention of pain sensitization. These findings contribute to the mechanism by which skeletal muscle grafts alleviate neuropathic pain and can be used as a sensory transmitter in conjunction with neural interfaces.

Neurostimulators, which deliver electrical energy to target nerves, represent a promising platform for modulating physiology in diseases ranging from hypertension to chronic pain. Despite their potential, most neurostimulator implants require open surgery to place hardware directly on small diameter and deep nerves, limiting both applications and adoption. Interventional radiology offers a powerful set of tools to overcome these barriers. Techniques such as percutaneous, endovascular, or port-based access, paired with computed tomography (CT), magnetic resonance (MR), fluoroscopic, or angiographic imaging, can be leveraged to enable minimally invasive targeting of deep nerves. Miniature electrodes and stimulators can be implanted precisely on organ-specific nerve branches or plexuses, providing selective control with fewer side effects. Concurrent advances in device design, including wireless power, millimeter-scale packaging, injectable and stent-like interfaces, and reliable anchoring and retrieval components, will facilitate minimally invasive neurostimulation therapies, especially for the autonomic system.

Abstract Electroceutical implants that deliver targeted neural stimulation have shown therapeutic potential for a wide range of neurological and peripheral disorders, yet wirelessly powering ultra-miniaturized, fully injectable systems remains a critical challenge. Here we report a Thread-like Injectable Neural TechnologY (TINY), powered via a differential tissue-coupled powering (DTCP) scheme. DTCP employs mid-frequency differential potentials applied across external electrodes on a compact, wearable transmitter to deliver energy through tissue to an ultra-miniaturized, thread-like implant that integrates a custom ASIC and PEDOT-coated receiver and stimulation electrodes. Benchtop experiments in agar phantoms characterize the power-transfer efficiency (PTE) and reveal that PTE increases with implant length while maintaining strong tolerance to angular misalignment. In vivo tests in rat hindlimbs further demonstrate wireless activation of the sciatic nerve through tissue at centimeter-scale depths, confirming effective transcutaneous energy delivery for neurostimulation. A 20-day implantation study shows stable positioning of the device with minimal tissue response, indicating excellent chronic compatibility. These findings address long-standing challenges in wirelessly powering injectable electroceuticals and establish DTCP as a scalable and alignment-robust powering strategy for future minimally invasive neuromodulation therapies.

Gastrointestinal (GI) dysmotility and associated conditions affect over 20% of population, yet pharmacological, behavioural, and surgical interventions offer limited therapeutic efficacy. Targeted electrical stimulation addressing underlying neuromuscular pathology stands to transform our ability to treat dysmotility. Here, we developed a closed-loop GI neuroprosthesis which activates or relaxes GI tract musculature through electrochemical stimulation in response to sensed food stimuli. We additionally describe a tool supporting minimally invasive endoscopically guided implantation that can penetrate the mucosa, accurately localize the submucosa, and safely deploy this device to directly interface with the enteric nervous system. The neuroprosthesis enables generation of coordinated peristaltic waves, significantly increasing the motility rate in a swine model of oesophageal and stomach dysmotility (p < 0.05, student’s t-test). Further, by directly modulating the myenteric plexus and thus mimicking meal ingestion, we induce peristalsis in a fasted state and achieve a metabolic response commensurate with a fed or satiated state. This neuroprosthesis and implantation platform expand opportunities in fundamental studies and treatments of metabolic and neuromuscular pathologies affecting the GI tract. Gastrointestinal motility disorders affect over 20% of the population, yet current therapies provide limited relief. Here, the authors show that in a swine model a closed-loop GI neuroprosthesis restores peristalsis and enhances metabolic responses via targeted electrical and chemical stimulation

While most oncologists know that many chemotherapies are dosed on a body surface area (BSA) basis, fewer know that the equations used to estimate BSA are based on a study done over 100 years ago using data from just 9 people. Moreover, two patients with the same BSA can have many factors, such as body composition and genetics, which can impact a drug’s pharmacokinetics and pharmacodynamics, resulting in worse therapeutic outcomes. To solve this problem, we developed a medical device that can personalize the dose of chemotherapy to the patient during an infusion center visit. Our medical device, which we call CLAUDIA (the Closed-Loop AUtomated Drug Infusion regulator) is a closed-loop drug delivery system that measures the concentration of drug and changes the infusion rate in real time to keep the concentration of drug within the therapeutic window. CLAUDIA uses high performance liquid chromatography-mass spectrometry (HPLC-MS) as the sensor, which allows it to be relatively easily translated to control many different drugs, either individually or in a combination chemotherapy regimen. We demonstrate CLAUDIA can control the concentration of 5-fluorouracil (5-FU) in rabbits, which were manipulated to capture the pharmacokinetic variability observed clinically. We then adapted CLAUDIA to also control the concentration of irinotecan, demonstrating its ability to be rapidly translated to additional chemotherapies. Finally, we perform a cost-effectiveness analysis that demonstrates that CLAUDIA is cost-effective compared to the current standard of care for drug dosing of 5-FU (i.e., BSA). Overall, CLAUDIA presents promising medical device that can personalize the dosing of chemotherapy, which may be able to improve the therapeutic outcomes for multiple chemotherapies. Citation Format: Louis DeRidder, Kyle Hare, Ted Smierciak, Mia Chao, Aaron Lopes, Josh Jenkins, Nina Fitzgerald, Emmeline MacPherson, Niora Fabian, Josh Morimoto, Jacqueline Chu, Ameya Kirtane, Wiam Madani, Keiko Ishida, Johannes Kuosmanen, Naomi Zecharias, Christopher Colangelo, Hen-Wei Huang, Makaya Chilekwa, Nikhil Lal, Shriya Srinivasan, Alison Hayward, Brian Wolpin, David Trumper, Troy Quast, Douglas Rubinson, Robert Langer, Giovanni Traverso. Closed-loop drug delivery system to personalize chemotherapy dosing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1847.

The etiology of chronic pain can be difficult to pinpoint, and the condition often resists many treatments. Conservative approaches using non-opioid medications often offer inadequate relief, while opioids pose significant risks of dependence and sedation, achieving on average 30% reduction in pain intensity.1 Despite the risks, pain management has historically relied heavily on opioids. With 20% of US adults experiencing chronic pain in 2021, the need for innovative treatments—ones that not only alleviate pain but also address its underlying causes—has become evident.2 In fact, recent data indicate that chronic pain has become a more common diagnosis than diabetes, depression, or hypertension, all of which may be linked to its development.3–5 As the complexity of chronic pain becomes more apparent, greater collaboration across pain-related specialties becomes essential for developing holistic solutions. The complexity of chronic pain arises from a variety of factors, including both physiological and social determinants of health. As a result, contemporary approaches integrate multiple pain-related specialties (Figure 1). In fact, the 2019 “Pain Management Best Practices Interagency Task Force Report” by the US Department of Health and Human Services endorsed multimodal and multidisciplinary strategies as the most effective treatments for both acute and chronic pain.6 Such programs offer a broad range of treatments including medications, restorative therapies, invasive interventions, and care that addresses the social and psychological aspects of pain (Table 1). These programs, despite variance in content and duration, consistently show significant improvements in pain, mood, daily activities, and quality of life over time.6–8 Building on this success, integrative therapies like acupuncture have gained acceptance among both patients and clinicians, with clinical evidence increasingly supporting their use in areas such as cancer pain management.9 At their core, these therapies combine conventional medicine with holistic practices that address emotional, mental, and cultural dimensions of healing, thereby addressing both the physical and non-physical contributors to pain and ultimately enhancing patient experience and outcomes. Disciplines and innovation. Interdisciplinary approaches and complementary therapies for acute and chronic pain. A growing number of institutions are driving advances in pain management by guiding innovators from idea to commercialization by offering educational, business, and financial support. For example, the Stanford Pain Relief Innovations Lab offers the “Empowered Relief” class, which disseminates holistic pain relief techniques that has been shown to be as effective as multiple cognitive behavioral therapy sessions. Similarly, the Harvard Medical Device Innovation Initiative supports student-led ventures such as Poly6 Biotechnologies, which developed implantable devices to prevent pain from abdominal and pelvic adhesions. Healthcare innovation challenges, such as those hosted by MIT Hacking Medicine, foster creative solutions for holistic pain management by bringing together diverse professionals and providing a platform to showcase their concepts. These initiatives help entrepreneurs transition their ideas from concept to commercialization, assisting them in securing the necessary funding and partnerships. For instance, the American Academy of Pain Medicine (AAPM) hosted 175 companies from 30 states and 15 countries at innovation challenges over the past 3 years, with finalists raising millions in funding through AAPM's support. Notable successes include Lutroo, which developed AI-enhanced pain imaging technology and received SBIR and NIH HEAL Initiative funding; Wellness Wits, a digital health solution for chronic pain, which partnered with IBM and scaled its operations; Vanish Therapeutics, which advanced its novel drug delivery systems with significant SBIR and venture capital funding; and FaraMed Tech, which is pursuing clinical trials for a wearable neuromodulation solution. These success stories illustrate how such initiatives help entrepreneurs overcome the critical challenges of early-stage startups (Table 2). Referenced weblinks stratified by section. Advanced diagnostic technologies (e.g., PET, MRI, EEG) and biomarkers have enhanced our understanding of pain processes and prevention. Recent pharmaceutical innovations, such as ultrasound-triggered local anesthesia and photoswitchable analgesics, enable more targeted drug delivery. Minimally invasive procedures—such as IntraceptTM, VertiflexTM, Reactiv8, Mild®, Painteq®, SIFix®, and Minuteman®—have been developed to improve lower back pain. Neuromodulation devices have evolved beyond traditional spinal cord stimulation to stimulation of the dorsal root ganglion and peripheral nerve, with closed-loop algorithms from companies like Abbott and Saluda Health. Despite these advances, challenges remain—device and drug parameters often require patient-specific titration, and 28% of individuals with implanted stimulators report insufficient pain relief.10 Additionally, 26% of these patients undergo surgical revision, wherein 5% involve device removal.10 These challenges highlight the need to improve the effectiveness and longevity of implanted devices. External stimulation devices, such as transcranial magnetic stimulation (TMS), transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), vibration therapy, and magnetic field therapy offer safe and cost-effective pain management, though further research is needed to refine their use. Specific products like Actipatch®, Omron Avail, and Cefaly offer relief for a variety of conditions, including musculoskeletal pain, chronic pain, acute pain, arthritic pain, and migraines, while VibraCool combines cold and vibration to stimulate the body’s natural pain-relieving pathways. Beyond physical pain management, online platforms address psychological and social dimensions of pain. Innovations like NeuroSphere™ and telemedicine software facilitate remote patient management, while virtual reality (VR) technology has helped shift pain perception by distracting users from discomfort. Emerging VR technologies range from simple apps to immersive full-body experiences, with options like Applied VR, Sana Health, Flowly, Headspace, and Mindmaze. VR has also shown potential to increase pain tolerance by downregulating nociceptive signaling and upregulating non-painful cognitive signals.11 Companies such as Lin Health, Override, Menda Health, and Upside Health are establishing new digital care paradigms for behavioral therapy and chronic pain management. Overall, these technologies not only provide new treatment options but also target previously underexplored causes of pain, offering more comprehensive approaches. Adequate funding and robust industry support are crucial for bridging the gap between technological advances and clinical management of chronic pain. In the United States, traditional funding sources like the National Institutes of Health (NIH) tend to prioritize conventional approaches, particularly those focused on opioids. For example, in 2023, NIH funding for opioid research, misuse, and addiction reached $1.8 billion, while research on peripheral neuropathy, neck and back pain, and fibromyalgia combined received only $300 million, with no reported funding for interventional pain medicine.12 While industry plays a role, they primarily step in for commercialization once early concepts prove viable, making government support critical for the initial stages of research. Public-private partnerships, such as the Innovative Medicines Initiative in the EU, which funds projects like EUROPAIN and NGN-PET, offer a balanced approach by providing a mixture of public and private funding from ideation to commercialization, helping navigate the crucial transition between public and private investment in technology development. Institutions like the University of Pittsburgh’s Center for Innovation in Pain Care and The Cleveland Clinic’s Pain Science Technology and Research (STAR) Lab exemplify U.S.-based innovation efforts driven by such partnerships. The complexity of pain demands the development of holistic approaches to pain management. To fully address this multifaceted issue, it is essential for stakeholders from various fields to unite and devise comprehensive strategies that encompass all aspects of pain care. Programs that connect clinicians, entrepreneurs, and patient advocates are crucial for fostering the growth and translation of new technologies into clinical practice. One avenue for such collaboration could be formalized consortia dedicated to pain management innovation, with shared funding and resources aimed at bridging the gaps between clinical research, industry advancements, and patient needs. Further, comprehensive interdisciplinary training for researchers and clinicians is necessary to create informed, well-rounded diagnoses and pain management plans. Such training could be structured around immersive, cross-specialty modules, allowing participants to engage directly with perspectives from fields related to pain management (Figure 1). Regulatory agencies pave the way for these collaborative innovations through up-to-date guidelines. For example, the FDA’s recent regulations encourage the development of non-opioid analgesics for acute pain, promoting safer and more effective alternatives. By incentivizing projects aligned with these guidelines, we could attract investments into non-opioid development labs, supporting cross-disciplinary teams focused on alternative pain relief options. Through concerted efforts from diverse sectors, we can transform pain management and improve the lives of millions suffering from chronic pain. There are no financial conflicts to disclose pertaining to the current submission. Dr Justin E. Bird consults for Stryker, Icotec, BrainLab and GT Medical Technologies. Dr Justin E. Bird also receives research funding support from Artidis RCTS #:00061874: Strategic Alliance—Artidis Alliance—Umbrella Protocol: Pancreatic, hepatobiliary, soft tissue sarcoma, chondrosarcoma, chordoma, and lung cancers. Dr Chris Gilligan consults for Mainstay Medical, Saluda and Iliad Lifescience and receives stock options from Mainstay Medical consulting and stock options. Stanford University receives revenue for continuing medical education on Empowered Relief (ER) instructor certification training provided to clinicians. Dr Darnall is Chief Science Advisor at AppliedVR, and her consulting role with this company (personal fees) is unrelated to the current work. Dr Darnall receives royalties for four pain treatment books she has authored or co-authored. She is the principal investigator for two pain research awards from the Patient-Centered Research Outcomes Research Institute, one of which is investigating the effectiveness of ER. Dr Darnall is a principal investigator for two NIH grants investigating ER's efficacy. Dr Darnall serves on the Board of Directors for the American Academy of Pain Medicine, the Board of Directors for the Institute for Brain Potential, and the Medical Advisory Board for the Facial Pain Association. Dr Darnall is a scientific member of the NIH Interagency Pain Research Coordinating Committee, a former member of the Centers for Disease Control and Prevention Opioid Workgroup (2020–2021), and a current member of the Pain Advisory Group of the American Psychological Association. National Institute on Drug Abuse K24 DA053564 (Darnall). Conflicts of interest: The authors do not have any relevant conflict of interest to disclose.

Body-coupled powering (BCP) is an innovative wireless power transfer (WPT) technique, recently explored for its potential to deliver power to cutting-edge biomedical implants such as nerve and muscle stimulators. This paper demonstrates the efficient technique of designing WPT systems embedding BCP via galvanic coupling (G-BCP). The G-BCP configuration utilizes two metal circular rings surrounding the body area of interest as the transmitter (TX) electrodes required for galvanic (differential) excitation and a wireless implant as the receiver (RX) equipped with two electrodes for differential power reception accordingly. By focusing on the unique advantages of this approach - such as enhanced targeting accuracy, improved power transfer efficiency (PTE), and favorable tissue penetration characteristics, G-BCP emerges as a superior alternative to traditional WPT methods. A comprehensive analysis is conducted to obtain the optimized device parameters while simultaneously allowing flexible placement of implants at different depths and alignments. To substantiate the proposed design concept, a prototype was simulated in Ansys HFSS, employing a multi-layered tissue medium of 10mm radius and targeting the sciatic nerve of a rat. Impressively, this prototype achieves &gt; 20% PTE at 1.25 GHz, with the implant (radius of RX electrodes = 1 mm) located 2 mm deep inside the tissue model having complex load impedance of Rload = 1000 Ohm and Cload = 5pF. Therefore, the G-BCP-based wirelessly powered microdevices are envisaged to be a key enabler in neural recording and stimulation, specifically for the peripheral nervous system, enhancing therapeutic outcomes and patient experiences.

Body-coupled powering (BCP) is an innovative wireless power transfer (WPT) technique, recently explored for its potential to deliver power to cutting-edge biomedical implants such as nerve/muscle stimulators. This paper demonstrates the efficient technique of designing WPT systems embedding BCP via galvanic coupling (G-BCP). The G-BCP configuration utilizes two metal circular rings surrounding the body area of interest as the transmitter (TX) electrodes required for galvanic (differential) excitation and a wireless implant as the receiver (RX) equipped with two electrodes for differential power reception accordingly. By focusing on the unique advantages of this approach—such as enhanced targeting accuracy, improved power transfer efficiency (PTE), and favorable tissue penetration characteristics, G-BCP emerges as a superior alternative to traditional WPT methods. A comprehensive analysis is conducted to obtain the optimized device parameters while simultaneously allowing flexible placement of implants at different depths and alignments. To substantiate the proposed design concept, a prototype was simulated in Ansys HFSS, employing a multi-layered tissue medium of 10 mm radius and targeting the sciatic nerve of a rat. Impressively, this prototype achieves $\gt 20 \%$ PTE at 1.25 GHz, with the implant (radius of RX electrodes $=1 \mathrm{~mm}$) located 2 mm deep inside the tissue model having complex load impedance of $R_{\text {load}}=1000 \Omega$ and $C_{\text {load}}=5 p F$. Therefore, the G-BCP-based wirelessly powered microdevices are envisaged to be a key enabler in neural recording and stimulation, specifically for the peripheral nervous system, enhancing therapeutic outcomes and patient experiences.

As the field advances with the introduction of a new generation of electrodes, the demand for refined injection methodologies becomes evident. These electrodes, frequently termed microdevices, are intricately microfabricated and require precise insertion into neural tissue. Despite the existence of conventional injection methods, there is a pressing need to formulate strategies aimed at minimizing the damage associated with the deployment of microdevices of varied sizes and configurations. In recognition of this need, the introduced technique can be applied for damage mitigation when injecting microdevices into brain tissue. We introduce a novel injection aid and describe an injection technique that results in reduced tissue damage. The damage of injecting into agarose and the brain, with and without the aid of a tool that creates microvibrations is evaluated. Cryosectioning data is presented to assess the damage caused by the injection, which was found to be 7.4% less when using microvibrations.

The emerging field of cancer neuroscience reshapes our understanding of the intricate relationship between the nervous system and cancer biology; this new paradigm is likely to fundamentally change and advance neuro-oncological care. The profound interplay between cancers and the nervous system is reciprocal: Cancer growth can be induced and regulated by the nervous system; conversely, tumors can themselves alter the nervous system. Such crosstalk between cancer cells and the nervous system is evident in both the peripheral and central nervous systems. Recent advances have uncovered numerous direct neuron-cancer interactions at glioma-neuronal synapses, paracrine mechanisms within the tumor microenvironment, and indirect neuroimmune interactions. Neurosurgeons have historically played a central role in neuro-oncological care, and as the field of cancer neuroscience is becoming increasingly established, the role of neurosurgical intervention is becoming clearer. Examples include peripheral denervation procedures, delineation of neuron-glioma networks, development of neuroprostheses, neuromodulatory procedures, and advanced local delivery systems. The present review seeks to highlight key cancer neuroscience mechanisms with neurosurgical implications and outline the future role of neurosurgical intervention in cancer neuroscience.

The agonist-antagonist myoneural interface (AMI) is an amputation surgery that preserves sensorimotor signaling mechanisms of the central-peripheral nervous systems. Our first neuroimaging study investigating AMI subjects conducted by Srinivasan et al. (2020) focused on task-based neural signatures, and showed evidence of proprioceptive feedback to the central nervous system. The study of resting state neural activity helps non-invasively characterize the neural patterns that prime task response. In this study on resting state functional magnetic resonance imaging in AMI subjects, we compared functional connectivity in patients with transtibial AMI (n = 12) and traditional (n = 7) amputations (TA). To test our hypothesis that we would find significant neurophysiological differences between AMI and TA subjects, we performed a whole-brain exploratory analysis to identify a seed region; namely, we conducted ANOVA, followed by t-test statistics to locate a seed in the salience network. Then, we implemented a seed-based connectivity analysis to gather cluster-level inferences contrasting our subject groups. We show evidence supporting our hypothesis that the AMI surgery induces functional network reorganization resulting in a neural configuration that significantly differs from the neural configuration after TA surgery. AMI subjects show significantly less coupling with regions functionally dedicated to selecting where to focus attention when it comes to salient stimuli. Our findings provide researchers and clinicians with a critical mechanistic understanding of the effect of AMI amputation on brain networks at rest, which has promising implications for improved neurorehabilitation and prosthetic control.

Image-guided tumor ablative therapies are mainstay cancer treatment options but often require intra-procedural protective tissue displacement to reduce the risk of collateral damage to neighboring organs. Standard of care strategies, such as hydrodissection (fluidic injection), are limited by rapid diffusion of fluid and poor retention time, risking injury to adjacent organs, increasing cancer recurrence rates from incomplete tumor ablations, and limiting patient qualification. Herein, a "gel-dissection" technique is developed, leveraging injectable hydrogels for longer-lasting, shapeable, and transient tissue separation to empower clinicans with improved ablation operation windows and greater control. A rheological model is designed to understand and tune gel-dissection parameters. In swine models, gel-dissection achieves 24 times longer-lasting tissue separation dynamics compared to saline, with 40% less injected volume. Gel-dissection achieves anti-dependent dissection between free-floating organs in the peritoneal cavity and clinically significant thermal protection, with the potential to expand minimally invasive therapeutic techniques, especially across locoregional therapies including radiation, cryoablation, endoscopy, and surgery.

BACKGROUND Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. METHODS We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). FINDINGS We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. CONCLUSIONS We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. FUNDING This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

Interdisciplinary strategies bridging oncology, neuroscience, bioelectronics and materials science will facilitate the development of next-generation therapies and devices for cancers of the central nervous system.

Postoperative ileus (POI) is the leading cause of prolonged hospital stay after abdominal surgery and is characterized by a functional paralysis of the digestive tract, leading to symptoms such as constipation, vomiting, and functional obstruction. Current treatments are mainly supportive and inefficacious and yield acute side effects. Although electrical stimulation studies have demonstrated encouraging pacing and entraining of the intestinal slow waves, no devices exist today to enable targeted intestinal reanimation. Here, we developed an ingestible self-propelling device for intestinal reanimation (INSPIRE) capable of restoring peristalsis through luminal electrical stimulation. Optimizing mechanical, material, and electrical design parameters, we validated optimal deployment, intestinal electrical luminal contact, self-propelling capability, safety, and degradation of the device in ex vivo and in vivo swine models. We compared the INSPIRE's effect on motility in models of normal and depressed motility and chemically induced ileus. Intestinal contraction improved by 44% in anesthetized animals and up to 140% in chemically induced ileus cases. In addition, passage time decreased from, on average, 8.6 days in controls to 2.5 days with the INSPIRE device, demonstrating significant improvement in motility. Luminal electrical stimulation of the intestine via the INSPIRE efficaciously restored peristaltic activity. This noninvasive option offers a promising solution for the treatment of ileus and other motility disorders.

Effective therapies for obesity require invasive surgical and endoscopic interventions or high patient adherence, making it challenging for patients with obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. We designed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill, an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release and yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake (~40%, P &lt; 0.0001) and minimized the weight gain rate ( P &lt; 0.05) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

Damage that affects large volumes of skeletal muscle tissue can severely impact health, mobility, and quality-of-life. Efforts to restore muscle function by implanting tissue engineered muscle grafts at the site of damage have demonstrated limited restoration of force production. Various forms of mechanical and biochemical stimulation have been shown to have a potentially beneficial impact on graft maturation, vascularization, and innervation. However, these approaches yield unpredictable and incomplete recovery of functional mobility. Here we show that targeted actuation of implanted grafts, via non-invasive transcutaneous light stimulation of optogenetic engineered muscle, restores motor function to levels similar to healthy mice 2 weeks post-injury. Furthermore, we conduct phosphoproteomic analysis of actuated engineered muscle in vivo and in vitro to show that repeated muscle contraction alters signaling pathways that play key roles in skeletal muscle contractility, adaptation to injury, neurite growth, neuromuscular synapse formation, angiogenesis, and cytoskeletal remodeling. Our study uncovers changes in phosphorylation of several proteins previously unreported in the context of muscle contraction, revealing promising mechanisms for leveraging actuated muscle grafts to restore mobility after volumetric muscle loss.

BACKGROUND: Enteric neuropathies, which result from abnormalities of the enteric nervous system, are associated with significant morbidity and high health-care costs, but current treatments are unsatisfactory. Cell-based therapy offers an innovative approach to replace the absent or abnormal enteric neurons and thereby restore gut function. METHODS: mouse, a model of colonic dysmotility, using either 1 (n = 12) or 3 (n = 12) injections (30 NS per injection) targeted longitudinally 1-2 mm apart. Functional outcomes were assessed up to 6 weeks later using electromyography (EMG), electrical field stimulation (EFS), optogenetics, and by measuring colorectal motility. RESULTS: recipient colon. Multiple injections of ENSCs resulted in a significantly larger area of coverage compared to single injection alone and were associated with a marked improvement in colonic function, demonstrated by (1) increased colonic muscle activity by EMG recording, (2) faster rectal bead expulsion, and (3) increased fecal pellet output in vivo. Organ bath studies revealed direct neuromuscular communication by optogenetic stimulation of channelrhodopsin-expressing ENSCs and restoration of smooth muscle relaxation in response to EFS. CONCLUSIONS: These results demonstrate that transplanted ENSCs can form effective neuromuscular connections and improve colonic motor function in a model of colonic dysmotility, and additionally reveal that multiple sites of cell delivery led to an improved response, paving the way for optimized clinical trial design.

Effective therapies for obesity either require invasive surgical or endoscopic interventions or high patient adherence, making it challenging for the nearly 42% of American adults who suffer from obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. Here we developed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill - an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release as well as yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake (~40%, p< 0.0001) and minimized the weight gain rate (p< 0.03) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

BACKGROUND While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal. METHODS We describe the design and validation of a platform technology for nerve regeneration and interfacing: adaptive, conductive, and electrotherapeutic scaffolds (ACESs). ACESs are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open surgical and minimally invasive percutaneous approaches. FINDINGS In a rodent model of sciatic nerve repair, ACESs significantly improved motor and sensory recovery (p < 0.05), increased muscle mass (p < 0.05), and increased axonogenesis (p < 0.05). Triggered dissolution of ACESs enabled atraumatic, percutaneous removal of leads at forces significantly lower than controls (p < 0.05). In a porcine model, ultrasound-guided percutaneous placement of leads with an injectable ACES near the femoral and cervical vagus nerves facilitated stimulus conduction at significantly greater lengths than saline controls (p < 0.05). CONCLUSION Overall, ACESs facilitated lead placement, stabilization, stimulation, and atraumatic removal, enabling therapeutic PNS as demonstrated in small- and large-animal models. FUNDING This work was supported by K. Lisa Yang Center for Bionics at MIT.

PURPOSE: While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration after injury to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal. METHODS: Here, we describe the design and validation of a new platform for nerve regeneration and interfacing: Absorbable, Conductive, Electrotherapeutic Scaffolds (ACES). ACES are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open and minimally invasive percutaneous approaches. RESULTS: In a rodent model of sciatic nerve repair, ACES significantly improved motor and sensory recovery (p < 0.05), increased muscle mass (p < 0.05), and increased axonogenesis (p < 0.05). Triggered dissolution of ACES enabled atraumatic, percutaneous removal of leads at forces significantly lower than controls (p < 0.05). In a porcine model, ultrasound-guided percutaneous placement of leads with an injectable ACES near the femoral and cervical vagus nerves facilitated stimulus conduction at significantly greater lengths than saline controls (p < 0.05). CONCLUSION: Overall, ACES facilitated lead placement, stabilization, stimulation and atraumatic removal enabling therapeutic PNS as demonstrated in small and large animal models.

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites 1 . Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage 2 . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

Localization and tracking of ingestible microdevices in the gastrointestinal (GI) tract is valuable for the diagnosis and treatment of GI disorders. Such systems require a large field-of-view of tracking, high spatiotemporal resolution, wirelessly operated microdevices and a non-obstructive field generator that is safe to use in practical settings. However, the capabilities of current systems remain limited. Here, we report three dimensional (3D) localization and tracking of wireless ingestible microdevices in the GI tract of large animals in real time and with millimetre-scale resolution. This is achieved by generating 3D magnetic field gradients in the GI field-of-view using high-efficiency planar electromagnetic coils that encode each spatial point with a distinct magnetic field magnitude. The field magnitude is measured and transmitted by the miniaturized, low-power and wireless microdevices to decode their location as they travel through the GI tract. This system could be useful for quantitative assessment of the GI transit-time, precision targeting of therapeutic interventions and minimally invasive procedures. Wireless ingestible microdevices can be tracked through the gastrointestinal tract of large animals in real time and with millimetre-scale spatial resolution by generating three-dimensional magnetic field gradients in the gastrointestinal field-of-view using high-efficiency planar electromagnetic coils, which encode each spatial point with a distinct magnetic field magnitude.