Challenges in IBD Research 2024: Novel Technologies

Abstract

Novel technology is one of the five focus areas of the Challenges in Inflammatory Bowel Disease (IBD) Research 2024 document. Building off the Challenges in IBD Research 2019 document, the Foundation aims to provide a comprehensive overview of current gaps in IBD research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of a multidisciplinary collaboration from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization.

Specifically, the Novel Technologies section focuses on addressing key research gaps to enable interception and improve remission rates in IBD. This includes testing predictions of disease onset and progression, developing novel technologies tailored to specific phenotypes, and facilitating collaborative translation of science into diagnostics, devices, and therapeutics.

Proposed priority actions outlined in the document include real-time measurement of biological changes preceding disease onset, more effective quantification of fibrosis, exploration of technologies for local treatment of fistulas, and the development of drug delivery platforms for precise, location-restricted therapies. Additionally, there is a strong emphasis on fostering collaboration between various stakeholders to accelerate progress in IBD research and treatment.

Addressing these research gaps necessitates the exploration and implementation of bio-engineered novel technologies spanning a spectrum from materials to systems. By harnessing innovative ideas and technologies, there’s a collective effort to enhance patient care and outcomes for individuals affected by IBD.

Introduction

Technology is a powerful force of progress in medicine, often offering solutions to clinical problems and challenges. In addition, technologies that have demonstrated benefits in areas outside of inflammatory bowel disease (IBD), and oftentimes even outside of medicine, have found applications and played major roles in advancing the care of patients with IBD. Challenges in IBD 2019 identified several gaps to be filled by novel technologies and offered potential pathways forward.¹ Several technologies were deemed to hold promise regarding improving the ability to accurately detect inflammation in a timely manner. Noninvasive technologies were favored for reasons of ease of adoption both by the patients and by clinicians. Among them were multiparametric magnetic resonance imaging (MRI) and multiparametric ultrasound, with both including contrast and elastography, multispectral optoacoustic tomography, and cross-sectional imaging with ultrasound, computer tomography (CT), nuclear medicine, positron emission tomography (PET), and molecular imaging.^2,3

There has been substantial growth in the area of ultrasound, with the emergence of small form factor ultrasound tools with enhanced resolution capabilities.^4-7 This has enabled improvements in precision imaging with use of contrast imaging and elastography to enable noninvasive evaluation of inflammation and fibrosis in IBD. With respect to molecular imaging, there has been some progress using labeled tracers to quantify fibrosis and inflammation.^8-10 For example, it was established that tissue remodeling during inflammation can result in overexpression of fibroblast activation protein (FAP), which can be targeted by specific FAP inhibitors (FAPIs). Utilization of radiolabeled FAPIs and PET allow imaging depiction of tissue remodeling.^9,10 Other studies have reported that prostate-specific membrane antigen (PSMA) can be expressed by inflamed cells in IBD, and PSMA-targeted radiotracer imaging with PET can identify areas of inflammation in the gut.⁸ Regarding biosensors for inflammation, there has been substantial progress in demonstrating and validating noninvasive continuous monitoring of sweat biochemistry through the use of perspiration-based wearable sensors.^11-14

Postsurgical anastomotic leakage and septic complications were identified as important gaps in 2019 and strategies were devised to overcome these complications.¹⁵ These areas pose considerable hurdles in terms of patient morbidity, necessitating further research to enhance our ability to prevent disease or its progression. In addition, the landscape of managing fistulizing Crohn’s disease (CD) of the perineum has witnessed notable advancements. For example, the ADMIRE-CD II trial evaluated the efficacy of mesenchymal stem cell therapy in perianal fistulizing CD. Although unsuccessful in meeting the primary efficacy end point, this trial contributed valuable insights.^16-18 The active ingredient of the intervention in ADMIRE-CD II trial is composed of stem cells; however, their migration away from the fistula tract potentially limited their efficacy. In response to this challenge, innovative technologies have emerged, demonstrating potential efficacy and addressing the pressing need for more effective interventions for perianal fistulizing CD.^19-22

Another gap identified in 2019 was drug delivery modalities and their role in disease management. Major strides have been made in this area since 2019, ushering in several advancements that clearly illustrate that in addition to effective small molecules and biologics, the field can benefit from smart targeting, sustained release characteristics, and delivery considerations. For example, a temperature-triggered gel for the local treatment of ulcerative colitis (UC) has been proposed,²³ and an autonomous mechanical capsule that uses reflected light²⁴ has started a phase 1 trial for colonic delivery of liquid tofacitinib. Additionally, decreasing side effects by targeted delivery of therapeutics to the site of inflammation has been a focal point of interest.²⁵ For instance, heparin-coated human serum albumin nanoparticles were developed for precise targeting of cells and areas of inflammation in the gastrointestinal (GI) tract.²⁵ These nanoparticles were able to carry both small molecules, as well as biologic drugs to the site of GI inflammation. The field has also witnessed breakthroughs in sustained release of active ingredients in the lumen of the GI tract, as well as in the gut wall at the site of a fibrotic stricture.^26,27

Background for Challenges in IBD 2024: Clinical Gaps Addressable by Technological Innovations

The range of IBD clinical manifestations, complications, and interventional opportunities is continuous and heterogeneous. Research areas and future advancements can be categorized into disease interception, remission, and restoration. The area of interception includes technology-based diagnostics and interventions at a preclinical stage to prevent symptoms from occurring and later complications from developing. The area of remission includes novel technologies deployed with the purpose of diagnosing, inducing, or maintaining remission. The main goal of these interventions is to minimize clinical symptoms and complications of IBD. The area of restoration includes novel technologies that are meant to restore normal functioning/homeostasis in the IBD patient. Technological innovations and approaches can be applied to all 3 of these categories. For example, biosensors, including implantable, point-of-care and/or wearables, bioelectronics, biomaterials, bioimaging, and sophisticated analytical methodologies are expected to improve disease interception, better classify the disease, and map remission and restoration interventions to the correct patient populations. Concomitantly, disease progression will be monitored and interpreted accurately, and the best therapeutic technologies will be deployed, leveraging biomaterials and other technologies for targeted drug delivery, sustained release platforms, combination therapies, and biorobots. Some of the foundational materials science aspects that guide development of novel technologies reside in the utilization of novel hybrid and active material systems that can be deployed for drug delivery and treatment of inflammation, as well as complications such as fibrosis, fistulas, and others. Finally, bioelectronics can be utilized for neuromodulation purposes to impact the brain-gut axis towards finding solutions for controlling the disease, namely restoration and achieving remission.²⁸ This technology can also be leveraged to treat chronic pain in quiescent disease. In terms of clinical areas that require a technology approach, we focus on 2 major areas: (1) disease detection; and (2) monitoring and treatment of complications from IBD.

Disease Detection and Monitoring

Novel technologies such as biosensors, biomaterials, bioelectronics, bioimaging, and analytical technologies to integrate information from a variety of environmental exposures and IBD patient sources are needed to advance our diagnostic capabilities. The promise of an interception approach is that the early and accurate diagnosis of disease will allow for timely management, even before clinical symptoms occur. Serum biomarkers have opened the door for prediction and prognostication of disease onset and natural history prior to symptom onset. For example, anti-integrin αvβ6 autoantibodies were higher in patients who developed UC up to 10 years before diagnosis in multiple longitudinal cohorts, and higher levels were associated with disease progression in patients with recently diagnosed UC.²⁹ In CD, increased intestinal permeability and altered intestinal barrier function assessed by the urinary fractional excretion of lactulose-to-mannitol ratio was associated with later development of the disease in children. Further, serum extracellular matrix protein 1, in addition to Saccharomyces cerevisiae antibodies and flagellin antibodies, have all been identified as potential serum biomarkers of progression to stricturing CD.^30,31

Once symptoms are present and IBD is diagnosed, accurate noninvasive monitoring of disease activity by novel technologies will allow timely intervention to lead to resolution of inflammation, better symptomatic control of disease flares, and minimization of tissue damage. This monitoring approach holds promise to prevent the accrual of bowel damage and complications and to enable sustained deep remission. Intestinal ultrasound (IUS) has been increasingly utilized as a noninvasive, point-of-care disease monitoring tool during routine clinic visits without the need for bowel preparation, oral contrast, or fasting and without substantial operator dependency among experts.³² Bowel wall thickness on IUS can be utilized as a surrogate for the more invasive and expensive endoscopic documentation of disease activity with potential use as an adjunct in CD clinical trials as both a screening tool and objective end point.^4,33 Directly monitoring early changes in bowel wall thickness on IUS in response to treatment in both CD and UC is highly predictive of endoscopic outcomes and, in children, may replace the need for repeated endoscopic assessment.^34-37 Moreover, improvements in MRI through the development of simple MRI indices for both luminal activity and healing and perianal fistulizing CD may enable more granular outcomes after treatment initiation.^38,39 For improved continuous disease activity monitoring to track flares prior to clinical GI symptom onset, wearable devices such as sweat sensors and biosensors have demonstrated the ability to noninvasively monitor biochemical inflammation such as C-reactive protein (CRP) and sweat calprotectin.^12,40 Lastly, serum proteins such as leucine-rich α2 glycoprotein and oncostatin-M may serve as more precise surrogates of endoscopic activity and treatment response compared with CRP and fecal calprotectin; however, further validation studies in larger, multicenter cohorts are needed.⁴¹ Ultimately, it is likely that a more precise and individualized methodology of noninvasive profiling of inflammatory activity will be able to monitor inflammation prior to and after clinical onset and better ensure resolution of inflammation, improving therapeutic efficacy and further altering the natural course of IBD.

Treatment of Complications in IBD

Treatment of complications in IBD represents a major source of healthcare costs and human suffering. Several clinical scenarios in IBD require an urgent technological focus. Among these, acute severe UC (ASUC),⁴² fibrostenosing⁴³ CD, and fistulizing CD are particularly challenging.⁴⁴ If amenable, anastomotic strictures in IBD are treated endoscopically by balloon dilation⁴⁵ or needle knife.^46,47 Wound healing mechanisms that led to excessive collagen deposition and stricturing in the first place, however, often starts anew after mucosal damage induced by balloon dilation or needle knife interventions.^48,49 Technological advancements in antifibrotic therapies are needed to modulate wound healing in a localized, sustained release approach. Additionally, fistulizing complications in IBD represent a vexing clinical problem in need of a technological solution. Antibiotics such as metronidazole and ciprofloxacin can improve fistula symptoms and may promote healing.^50-53 However, long-term antibiotic therapy can cause clinical side effects, antimicrobial resistance,⁵⁴ and Clostridioides difficile diarrhea.⁵⁵ Antitumor necrosis factor (anti-TNF) drugs demonstrate a significant positive effect on fistula closure; for example, a 5 mg/kg dose of infliximab results in 55% fistula closure rates after 6 months.^56,57 Nevertheless, almost half of patients still have open fistula tracts.^56,58-60 Due to the current lack of effective treatments for perianal CD, surgical approaches are often required. Setons, which are thin surgical threads, can be used to improve drainage from fistula tracts and show improved efficacy when used in conjunction with infliximab.⁶¹ More complex surgeries can be employed including fistulotomy, advancement flap, and ligation of the fistula, but even after surgery, only 34% of patients gain permanent fistula closure.^62,63 Alternatively, fibrin glue has been employed as a fistula filling material, but it is susceptible to infection and dislodgement due to poor wall integration.^23,25,64 Decellularized porcine scaffolds have also been used as fistula plugs, but have a roughly 50% failure rate, in part due to abscess formation.⁶⁵ Beyond plug materials, mesenchymal stem cell delivery has been employed clinically, which promoted healing in patients with perianal fistulas due to CD.⁴⁸ However, a lack of proper scaffolding for these cells likely reduces their retention in the fistula site and overall efficacy.^66,67 In response, recent research approaches aim to enhance the properties of filling materials and improve clinical outcomes for CD perianal fistula patients.

In the current publication, we identify gaps in the current management of IBD and technological solutions to address these gaps. We organize the identified gaps and corresponding technology along the coordinates of disease interception, remission, and restoration.

Technologies to answer needs in disease interception are needed to provide continuous real-time monitoring, such as biosensors and bioelectronics that can be engineered to measure environmental factors and biomarkers to enable a comprehensive surveillance of these factors prior to the onset of clinical symptoms. Moreover, wearables could also collect and integrate a variety of inputs to provide an ongoing, real-time assessment of disease activity, which would be valuable in managing remission. Importantly, implantable biosensors and bioelectronics may obviate the need for time-consuming and expensive testing, as well as perform a real-time evaluation of remission/flare continuum. Analytical methods, including machine learning and artificial intelligence, can provide methodologies to integrate a variety of inputs (patient reported outcomes, large datasets, cohorts, biorepositories, as well as electronic medical record stored laboratory results, pathology, clinical data, and others) to build better disease outcome prediction models that, by extension, would clarify novel points of intervention.

The first step in improving disease remission is to initially define and then longitudinally monitor tissue damage and extent of disease progression through bioimaging and analytical methods. Understanding how imaging can directly monitor morphological changes in the bowel as a predictor of treatment response and guide treatment optimization is needed to improve tight control monitoring strategies to achieve higher rates of remission with currently available therapies. Magnetic resonance imaging and US (nonionizing radiation imaging methodologies) are replacing old methods (such as the small bowel follow-through and CT scans) allowing for repeated imaging without ionizing radiation exposure, allowing for repeated assessments of the bowel to be incorporated into trials to understand how current treatments modify disease. Novel imaging methodologies to perform digital pathology or to assess bowel distensibility and bowel fibrosis are needed.

Drug-Targeting Technologies

Drug-targeting technologies are needed for the delivery of effective drugs directly to the affected area of the GI tract or even cells of interest to improve disease remission rates. The duration of pathological processes needs to be matched by the duration of drug action. For example, wound healing that follows an endoscopic dilation of a stricture or the creation of a new surgical anastomosis needs to be matched to the duration of a locally delivered antifibrotic. Similarly, the degree of mucosal inflammation needs to be temporally matched by the delivery of a sustained action formulation. These examples, and others, argue for a renewed effort to develop sustained drug release technologies. A fresh perspective on novel drug discovery efforts in IBD is also necessary. While some drug therapies are not effective in a subset of patients, and other drug therapies lose effectiveness over time, most anti-inflammatory therapies in IBD demonstrate a clinically significant, albeit not complete, efficacy in IBD patients. Therefore, combination therapies that include an existing anti-inflammatory strategy that demonstrates some efficacy, coupled with a novel, targeted, locally acting therapeutic may result in long-term remission. Biorobots represent a novel field that is based on robotics and materials research, which includes autonomous devices able to deliver drugs within the GI tract of patients with IBD. These devices range in size from submillimetric to a few centimeters.^68-70

Another area of promise is the design of local drug delivery devices, including implantable devices, drug patches, stents, and others. Biodegradable, endoscopically placed stents can be envisioned to deliver drugs locally for a predetermined duration without requiring subsequent removal. Such local delivery devices may find applications in areas of inflammation or strictures in the GI tract. An area of technological improvement could be mitigation of stent migration, as well as the identification of biomaterials necessary for bioresorbable and drug-eluting stents. Another technology that will likely play a role is US contrast for targeted drug delivery to diseased areas of bowel.⁷¹

Restoration

Restoration is an area of intense technology research that is meant to restore normal functioning of the IBD patient. Biomaterials represent an exciting area of concentrated investigation, with application to perianal and luminal fistulous tracts in patients with IBD. There is growing realization that a natural scaffold (such as human placenta material²¹) or a bioengineered scaffold (containing nanogels, nanofibers, and other materials) is required for tissue healing, recruitment of patient cells into the area of the fistula, and for the sustained release of stem cells or stem cell products locally. These multifunctional hydrogel materials can display cell-responsive degradation mechanisms,⁷² antimicrobial properties,⁷³ and stem cell–based healing cues.^22,74,75 Biomaterials can also serve as drug delivery vehicles to enable localized release of bioactive agents and reduce potential systemic side effects. Hydrogels have been developed that release anti-inflammatory drugs,^76,77 antioxidants,^78-81 antibiotics,⁸² and immune-modulating drugs.^83,84 Several of these platforms have promising preclinical results that could be leveraged in the future to improve restoration efforts in fistulizing CD.

Gaps and Priority Actions (Figure 1)

Figure 1.

Current research gaps and priority actions to leverage technological innovation to deliver improved care to IBD patients.

Gap 1. Tests Predictive of Disease Onset and Progression

• Priority action 1: Measure biological changes preceding disease onset in real time.

  • Biosensors: Implantable or wearable devices to monitor inflammation in real time and environmental triggers of disease onset, progression, and relapse; continuous, remote, point-of-care monitoring is favored for optimal disease interception and remission. Biosensors facilitate decision-making processes of when to start medical management and potentially guide the type of management.

  • Biomaterials for implantable or wearable devices to better quantify and monitor inflammation.

• Priority action 2: Identify and quantify fibrosis more effectively.

  • Bioimaging technologies (MRI, molecular imaging, PET, elastography, and other technologies)

  • Biosensors and biomaterials to allow monitoring of fibrosis development.

• Priority action 3: Integrate machine learning and other artificial intelligence techniques.

  • Integrate information from biosensors, clinical-grade imaging, patient-reported symptoms to enhance detection of flares and prevent or treat fibrosis/stenosing/bowel obstruction or penetrating complications.

  • Build decision support systems for automated medical diagnosis and management plan. Possible application could be support systems for clinicians to provide best tailored management.

Gap 2. Novel Therapies for Specific Phenotypes

• Priority action 1: Develop drug delivery platforms for time and location-restricted therapies.

  • Inflammation-triggered and GI tract-restricted targeted drug delivery platforms for oral administration and to prevent side effects of systemic bioavailable therapeutics.

  • Ultrasound contrast-drug delivery with pulsed ultrasound over the region of interest to locally release the drug.

• Priority action 2: Identify technologies for treatment of fibrosis in the GI tract.

  • Materials, devices, and endoscopic approaches to locally treat fibrostenotic strictures, sustained release, locally active therapeutics. Fibrosis and strictures in IBD are localized complications, therefore locally delivered active pharmacological ingredients and small molecules at time of endoscopy is favored.⁸⁵

  • Drug delivery platforms that target areas of fibrosis when delivered orally or by other systemic routes of administration.

• Priority action 3: Explore technologies for local treatment of fistulas.

  • Biomaterials (nanofiber, nanogel, others) that would allow fistula tract repair, with little to no immunogenicity, high tissue regeneration, timely material biodegradability, and delivery ability in a sustained fashion of small molecules or stem cell products to the affected area.

• Priority action 4: Establish technologies to address motility alterations.

  • Application of noninvasive neuromodulation to modulate either system-wide or local gut neuroimmune interfaces to address inflammation and pain.

Gap 3. Collaborative Translation of Science to Novel Diagnostics, Devices, and Therapies

Such change requires platforms to allow seamless collaboration between bioengineers and clinicians and are urgently needed to codevelop a shared set of tools, collaboration frameworks, and goals.

• Priority action 1: Build platforms for collaboration between stakeholders.

• Priority action 2: Establish mechanisms to share manufacturing and regulatory expertise, including drug repurposing, polymeric drugs, and complex device-cell therapeutics.

• Priority action 3: Determine platforms and conferences to expand knowledge regarding regulatory pathways (FDA navigation), test and medical device development, medicinal chemistry, pharmacokinetics and pharmacodynamics, and toxicology as they pertain to advancing novel diagnostics, devices, and therapeutics to patients.

Conclusion

The transformative role of technology in the realm of medicine, particularly within the context of IBD, cannot be overstated. In this current update, “Challenges in IBD 2024,” we propose 3 priority areas with focused actionable plans. We propose an interception goal focused on the development of novel technologies for early detection of biological changes preceding symptom onset, in addition to technological advances made towards an earlier and more precise diagnosis. Towards this end, technologies leveraging the underpinning in bioelectronics, biosensors, and bioimaging need further advancements to specific aspects of identification of inflammation and tracking the progress of inflammation with noninvasive approaches. We also propose a remission goal, involving drug delivery modalities, underscoring the ongoing efforts to enhance treatment outcomes. Lastly, we propose a restoration goal, encompassing technologies for assessing and treating complications, including postsurgery, reflecting a commitment to optimize patient care and restoration of functioning through advanced techniques. This goal finds its underpinning in developing novel biomaterials in conjunction with bioelectronics that can be used to restore GI structure and function. Principles of bioimaging, biomaterials, biorobots, and analytical methods will be integrated to address the current needs of precision medicine and personalization of outcomes. As technology continues to evolve, the synergy between innovation and patient needs in IBD promises a future where precision and efficacy define the standard of care, ensuring optimal well-being for individuals affected by these conditions.

Supplement Sponsorship

This article appears as part of the supplement “Challenges in IBD Research 2024,” sponsored by the Crohn’s & Colitis Foundation.

Conflicts of Interest

S.P.: co-founder of Enlisense LLc with equity interest

R.K.C. has received income for consulting and participation in advisory boards for Abbvie, Adiso, BMS, Fresenius Kabi, Fzata, Janssen, Magellan Health, Option Care, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, Sebela, and Takeda, has a research grant with Janssen, is a member of the Executive Committee for the IBD Education Group, and is Scientific co-director of the CorEvitas registry.

M.T.D. consultant for neurologica corp., a subsidiary of Samsung electronics co ltd.

R.W.S. RWS has investigator-initiated research support from Janssen Research & Development, Bristol Myers Squibb, and Abbvie. R.W.S. has served as a consultant or on advisory boards for AbbVie, Bristol Myers Squibb, CorEvitas, Eli Lilly, Exact Sciences, Gilead, Genentech, Janssen, Pfizer, and Takeda; holds intellectual property on cross-sectional imaging and endoscopic analysis technologies licensed by the University of Michigan to AMI, llc, and EIQ, llc with an equity interest in PathwaysGI, Inc.

K.A.C.: Johnson & Johnson Advisory Board

F.M.S is a consultant for Feldan Therapeutics, DEKA Biosciences, HydroGene, and ImYoo and receives grant funding from the NIH and the Helmsley Trust

Authors who are also on foundation staff: A.C.M., N.M.J.S., R.W.

All other authors have no conflicts to declare.