Next Generation Drug Delivery: The Spatiotemporal On-demand Patch (SOP )

Next Generation Drug Delivery: The Spatiotemporal On-demand Patch (SOP )
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Transdermal drug delivery has been a cornerstone in medical treatments, with an ever-pressing need for improvements in precision and personalization, especially given the dynamic nature of differing disease progression from patient to patient, such as neurodegenerative, autoimmune, and endocrine diseases. While traditional methods, such as hypodermic needles, have served their purpose, they come with limitations that hinder widespread adoption and patient compliance. Issues of safety, discomfort, and the requirement for skilled personnel have always been at the forefront of the concerns for traditional transdermal drug delivery methods.

Our development of the Spatiotemporal On-demand Patch (SOP) marks a significant leap forward in addressing the issues associated with traditional transdermal drug delivery methods, specifically the perennial challenges of ensuring patient adherence and the need for real-time, active control of pharmaceutical treatments for personalized healthcare. Our device integrates drug-loaded microneedles with biocompatible metallic membranes such as gold, as seen in Figures 1a and 1b. When the membranes are exposed to a DC potential, crevice corrosion occurs, facilitating the membrane's degradation (Figures 1c and 1d) and allowing for the controlled release of the drug housed within the microneedle. This high level of control is crucial for targeting medications precisely to where and when they are needed, down to less than 1 mm² of the targeted area, with rapid activation achievable within 2 minutes and induced immune responses comparable to traditional implants.

Figure 1. Spatiotemporal on-demand patch for wireless, active control of drug delivery. a. Schematic illustration highlighting the construction of a wirelessly controlled spatiotemporal on-demand patch (SOP) for high-precision drug delivery. The SOP features two main components: i) an array of drug-loaded microneedles protected by active encapsulation that exploits electrochemically triggered crevice corrosion, for on-demand drug delivery; ii) a near-field communication (NFC) module assembled on a soft printed-circuit board for wireless control. b. Exploded view of the drug-delivery interface of the SOP, including a PDMS encapsulation, an electrically triggerable gold (Au) coating, drug-loaded microneedles based on poly(D, L-lactide-co-glycolide) (PLGA), and a PLGA substrate. c. Schematic illustration showing the process of electrically controlled on-demand drug delivery from an individual microneedle. i) Standby stage where an encapsulation layer protects the microneedle from releasing drug. ii) Transitioning stage where an electrical trigger initiates crevice corrosion of the encapsulation layer to expose drug-loaded base. iii) Releasing stage, where the exposed base starts to release drugs. d. Schematic illustration demonstrating the capability of spatiotemporal control of releasing profile from the SOP. i)  Deploying an SOP at the skin interface. ii)- iv) Communicating with the NFC module of the SOP enables active control of drug release for each individual microneedle. e. Optical images of the multi-domain SOP undergoing a sequential electrical trigger. The domain triggered at each stage is labeled by red hexagonal dashed frames—scale bar: 5 mm. f. Schematic illustration showing the sequential electrical-triggering schedule on the multi-array SOP. The electrical triggering uses a DC voltage of 2.5 V for ~ 30 s. The schematics from Stage 0 to Stage iv correspond to the images in e.

Our study shows that the application of the SOP in medical treatments is feasible. Notably, we showcased the SOP's effectiveness in enhancing the onset of sleep in mice, where the programmed release of exogenous melatonin in mice's medial prefrontal cortex led to improved sleep patterns, highlighting its potential in both research and clinical settings. Furthermore, we demonstrated an innovative design and fabrication process that is highly customizable and scalable to meet a wide range of pharmaceutical needs and has the potential to improve patient adherence and medical precision significantly.

At the core of the SOPs functionality is the ability to electrically trigger drug release from microneedles, each potentially loaded with different drugs or concentrations, as represented by Figures 1e and 1f. This ability is pivotal for diseases that require quick adaptation in treatment strategies, allowing for the delivery of multiple therapeutics in a controlled and localized manner. By activating individual microneedles, the SOP can target specific tissue with precise doses, facilitating a tailored treatment regimen that can dynamically change over time or in response to a patient's condition. The SOP's design, therefore, not only ensures that drugs are delivered precisely where and when they are needed but also allows for the customization of therapy to the individual's changing needs, marking a potential advancement in personalized medicine.

The device's ability to provide multifunctional operations, including drug release and electrical stimulation (ES) from the same interface, further underscores its potential as a versatile tool in personalized medicine. This innovative feature could mainly be beneficial in treating neurological injuries, including peripheral nerve injuries (PNIs). PNIs are notoriously challenging to treat due to their propensity to lead to severe sensorimotor impairment and chronic pain. The treatment of PNIs often requires a multifaceted approach that includes pharmacological treatments, physical therapies, and surgical interventions, each with their respective limitations.1

Electrical stimulation has been recognized as a valuable method for promoting axonal regeneration and functional rehabilitation post-PNI. It has been shown to improve neurological function, expedite nerve regeneration, and mitigate neuropathic pain by influencing various physiological processes, including the reduction of atrophy in denervated skeletal muscle, inhibition of synaptic stripping and apoptosis, and modulation of sensory abnormalities.2 However, ES, alongside pharmaceutical methods, such as neural growth factors and steroids, has been traditionally limited, mainly due to challenges in maintaining effective drug concentrations at the target site.3

The SOP's integration of drug delivery with ES is particularly promising in this context. By combining pharmacological and electrical stimulation therapies, the SOP could provide a more comprehensive and effective treatment regime for PNIs and other neurological disorders by maintaining proper drug concentration at the injury site while delivering effective ES. While this adjunct treatment method still needs further research, the SOP could facilitate research into new treatment paradigms by allowing for the simultaneous application of pharmaceutical and electrical therapies, potentially uncovering synergistic effects that could benefit the treatment of PNIs.

Furthermore, the SOP could enhance the treatment of chronic episodic diseases by potentially integrating into closed-loop systems that can detect and respond to medical emergencies with appropriate pharmaceutical interventions. Such systems are particularly valuable for conditions like asthma and epilepsy, where timely and precise treatment can not only save patients' lives but could alter disease outcomes and improve quality of life.

In epilepsy, an increase in the likelihood and intensity of subsequent seizures with each episode has been observed, influenced by the duration of the seizures. This kindling-like progression, where seizure activity leads to stronger seizures, is noted in some types of human partial epilepsy.4 Understanding this kindling-like progression suggests that early and precise intervention during initial seizures might help mitigate the progression of epilepsy. While further evidence is required to confirm this theory, the incorporation of sensing technologies into the SOP for early seizure indication, followed by the immediate application of anti-epileptic medications, could feasibly disrupt the seizure mechanism, thereby possibly reducing the incidence and intensity of subsequent seizures.

Similarly, the ability to immediately respond to the onset of an asthmatic episode is crucial for patients with asthma. Episodes, particularly severe ones, can lead to pulmonary fibrosis, a condition characterized by the thickening and scarring of lung tissue, thereby exacerbating respiratory difficulties and increasing treatment resistance.5 Given scarring can occur at the early stages of asthma, with the ability to rapidly detect an asthma attack's onset and deliver bronchodilators or anti-inflammatory medications, the SOP could not only address the immediate symptoms but also potentially slow the progression of pulmonary fibrosis, enhancing the patient's respiratory function and response to treatments over time.

In conclusion, we hope the SOP will revolutionize drug delivery through precise control and rapid activation. This advanced capability, demonstrated in sleep studies with mice, shows great promise in enhancing treatment effectiveness and opens new avenues for customizable pharmaceutical applications, improving patient adherence and precision in medical treatments. Furthermore, its multifunctional design is particularly valuable in treating neurological diseases and injuries. The SOP's integration into closed-loop systems for immediate detection and response to medical emergencies also presents a transformative approach to managing chronic episodic diseases such as asthma and epilepsy. By rapidly addressing medical episodes, the SOP could treat conditions and potentially alter disease progression, offering a novel option in chronic illness management. Overall, we hope the SOP is more than a technological advancement but rather a significant shift towards proactive, precise, and transformative healthcare solutions.

 

References

  1. Hussain, G. et al. Current status of therapeutic approaches against peripheral nerve injuries: A detailed story from injury to recovery. International Journal of Biological Sciences 16, 116–134 (2020).
  2. Chu, X.-L. et al. Basic mechanisms of peripheral nerve injury and treatment via electrical stimulation. Neural Regen Res 17, 2185–2193 (2022).
  3. Lopes, B. et al. Peripheral Nerve Injury Treatments and Advances: One Health Perspective. Int J Mol Sci 23, 918 (2022).
  4. Bertram, E. The Relevance of Kindling for Human Epilepsy. Epilepsia 48, 65–74 (2007).
  5. Savin, I. A., Zenkova, M. A. & Sen’kova, A. V. Bronchial Asthma, Airway Remodeling and Lung Fibrosis as Successive Steps of One Process. International Journal of Molecular Sciences 24, 16042 (2023).

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