Implantable technologies have come a long way over the years, and advancements in micro and nanotechnologies have helped device developers continue to push the envelope even further. Within the realm of drug delivery, advances in nanotechnologies have consistently improved patient outcomes by enabling sustained drug delivery to help treat chronic conditions. These scalable technologies have even offered localized drug delivery that can further improve bioavailability.


While many of these technologies offer a variety of opportunities, we’re still eagerly awaiting to see the impact of these advancements once they’re actually leveraged against implantable device technologies. Many believe that recent micro and nanotechnology advancements could pave the way for things like increased local administration of drugs, zero-order release kinetics, more efficacious use of existing drugs with great bioavailability, personalized poly-pharmacy, and even on-demand drug delivery.


To better understand some of these potential outcomes, MD+DI checked in with Murty Vyakarnam, PhD, an innovator in medical devices, drug-device combination products, and biomaterials. He previously served as head of Global R&D for medical devices and pharma solutions for the newly created Lubrizol Lifesciences business unit, a Berkshire Hathaway company. He’s also spent time as director of research and development for Advanced Technologies & Regenerative Medicine.


Vyakarnam has spent years directing research and overseeing successful product launches for several Johnson & Johnson companies, so he’s had his finger on the pulse of drug-delivery system development for quite some time. He’ll be speaking at the BIOMEDevice conference in San Jose in the December 6 talk, “Micro/Nano Technologies for Implantable Drug Delivery Systems.”


MD+DI: For starters, can you talk a little about some of the recent advancements within the realm of micro and nanotechnologies that could potentially set the stage for next-gen implantable drug delivery systems? What impact could some of these recent advancements have on these implantables?


Vyakarnam: Advances in bio-microelectromechanical systems (BioMEMS) and biosensors have led to several miniaturized medical devices and drug-delivery systems including microfluidics and lab-on-chip diagnostic devices, diagnostic wearables, miniaturized robotics, and implants with closed-loop drug delivery systems. Advances in the micro and nano particle technologies have led to numerous injectable drug delivery systems. Injectable nanoparticle-based drug delivery with tissue targeting is providing many promising solutions in tumor treatment and continues to be a very active area of research. Injectable microparticle systems or gels that can become long-acting drug-delivery depots have provided significant advances in the treatment of various conditions including pain and schizophrenia. A third underlying front involves the advances in materials science especially bioresorbable polymers and hydrogels where the properties can be tuned with new chemistries for better formulation with drugs and processed in unique ways, including 3D printing with minimal loss in potency of the small molecule or biologic therapeutics.


Increasingly the discovery of several new poorly soluble drugs and/or biologics have tremendously expanded the need for drug-delivery technologies with alternate routes of administration beyond the traditional oral and parenteral routes. Implantable drug-delivery systems deliver pharmaceutics locally, targeting the tissue/organ [and] minimizing the side effects of systemic delivery. It is the convergence of the pharmacologic need for alternate routes of administration for the new therapeutics combined with the advances in engineering solutions that is driving the development of next-generation implantable drug-delivery systems.


Implantable drug-delivery systems (IDDS) are playing a key role in the treatment and management of several chronic conditions including diabetes, oncology, ocular disorders, cardiovascular conditions, and women’s health. Managing chronic diseases with progressively debilitating outcomes can be challenging with poor compliance, and in those situations IDDS might be the only hope to slow or reverse the disease progression. Ultimately, implantable drug-delivery devices with precision-medicine approaches will improve the management of patient health, increase survival rates, and lower healthcare costs.


MD+DI: What kind of advancements are being made for sustained drug-delivery platforms that could help treat chronic conditions and potentially diseases?


Vyakarnam: Below are a few examples of advances being made in the treatment or management of chronic diseases using sustained drug-delivery platforms:


Osteoporosis. Osteoporosis is a disease in which bones deteriorate or become brittle and fragile due to low bone mass and bone tissue loss. This affects approximately 10 million Americans, predominantly post-menopausal women. One treatment option for patients with high risk of bone fracture is a daily injection of human parathyroid hormone fragment (marketed as Teriparatide), which can last for 2 years. However, adherence to daily injection therapy is a significant problem. MicroCHIPS (now part of Keratin Biosciences) developed a groundbreaking MEMs-based implantable drug-delivery chip to deliver Teriparatide. This implantable multi-well drug-delivery chip made of silicon is wirelessly controlled and programmable. Unlike passive drug-delivery implants, MicroCHIPS’s implants can respond to wireless signals [that] can activate, deactivate, or modify the frequency or dosing of the drug [for] up to several years. The efficacy of this microchip approach was demonstrated in a clinical trial in postmenopausal women with osteoporosis. The microchip implants delivered the same therapeutic level of drug to increase bone mass as was achieved with daily injections. This microchip technology is also being developed for several other chronic conditions including diabetes, contraception, and drug delivery to tumors.
Mental disorders. Less-than-optimal treatment options and inadequate resources for patient care have led to a national crisis in mental health, especially with opioid addiction. Recently, FDA approved Probuphine (Titan Pharmaceuticals), a six-month implant that delivers buprenorphine for treatment maintenance of opioid addiction. This miniaturized drug delivery implant to treat opioid addiction is a great way to address this epidemic as the very nature of this chronic condition makes patient compliance a big challenge. This implant is injected in an office setting but needs to be removed after six months. BioCorRx is developing a naltrexone implant that is bioresorbable, which will be an advantage over Probuphine, as the implant does not have to be removed. In the last decade or so, great strides have been made in treating schizophrenia using long-acting antipsychotics drugs formulated with PLGA (poly {lactic-coglycolic acid}) microparticles as an injectable depot. The prevalence of co-morbid conditions in mental health opens the doors for dual drug-delivery depots. This would be a further advancement in implantable drug-delivery systems that can potentially address more than one underlying condition, e.g. addiction and schizophrenia.
Cardiovascular Diseases. Another class of drug-delivery implants that were transformational in the field of interventional cardiology are the drug-device combination products. In this class of implants there is usually a physical device, like a stent, that has a mechanical function and a drug-delivery depot (usually a coating) that delivers the drug and addresses the underlying pathology. This was pioneered by JNJ’s Cypher drug-eluting stent using sirolimus to treat restenosis. Since then there have been several other drug-device combination products. More recently, drug-eluting balloons (CR Bard’s Lutonix and Medtronic’s In.Pact) using paclitaxel have proven to be efficacious in treating peripheral artery disease (PAD). Along the same lines, but a first for sinus tissue, PROPEL sinus implants (Intersect ENT) was recently introduced. These offer localized, controlled drug delivery of an advanced corticosteroid (mometasone furoate) with an anti-inflammatory directly to the sinus tissue. Here the miniaturized spring-like bioresorbable implant maintains the surgical opening, prop opens the ethmoid sinus, and gradually delivers the drug directly to the sinus lining as the implant dissolves.
MD+DI: What kinds of design and material options do you see driving innovation for implantable drug-delivery systems over the next few years?


Vyakarnam: The first thing to consider in developing implantable drug-delivery systems for sustained delivery is the route of administration. Alternate delivery routes to deliver drugs that are being increasingly considered are injectable depots, targeted delivery to tumors, surgical site, ocular, pulmonary, nasal, vaginal, transdermal, etc. These delivery routes provide the developers of the implantable drug-delivery systems with several design options.


Biomaterials, especially polymers, play a critical role in both the formulation of the drug as excipients as well as in the development of a wide variety of implantable devices for sustained drug delivery. Historically, the long-term implants were made with bio-durable polymers like silicones and ethylene vinyl acetates (EVA). Silicones have long been a material of choice for drug delivery given their extreme chemical inertness and the ability to compound various drugs within the matrix. EVA is also finding use in drug delivery application due to its ability to control drug-release kinetics by varying the vinyl acetate content. More recently, polyurethanes are also being considered for long-term drug-delivery implants as they provide greater degrees of freedom in designing the polymer to tailor the drug-release kinetics.


In many situations, it is more attractive if the long-term implant does not have to retrieved. Here the advantages of using bioresorbable polymers for the drug-delivery implant goes without saying. Bioresorbable polymers such as PLGA have the ability for control release of drugs while essentially “dissolving away” by hydrolysis to produce lactic and glycolic acid. These polymers have also been considered for numerous implantable systems including injectable microparticle and injectable depots. Other resorbable polymers that are being considered include poly caprolactone and tyrosine derived polycarbonates. The field of bio-resorbables continues to be an area of active research to tailor biodegradation rates [and] induce degradation on stimuli like pH, enzymes, or externally induced triggers.


As noted below, the advances in BioMEMS and biosensors are also driving innovation in the closed-loop injectable drug-delivery systems.


MD+DI: In a broader sense, how do you think advanced drug delivery systems could impact things like on-demand drug delivery and personalized polypharmacy?


Vyakarnam: The holy grail is an implant that can sense a condition or detect a leading biomarker that signals a need for intervention and accordingly triggers the release of a drug at the right dosage, time, and duration to intervene – essentially an on-demand drug-delivery system. The efficacy of pharmaceutical treatments can be greatly enhanced by physiological feedback from the patient using biosensors. After decades of development, great advances have been made in treating diabetes with a closed-loop insulin pump delivery. Medtronic introduced MiniMed 670G, the first hybrid closed-loop system that helps in preventing hypoglycemic and hyperglycemic conditions with better outcomes in HbA1c readings. The development of reliable continuous glucose monitoring was critical for the successful automation of insulin delivery. It was the total system of improved continuous glucose sensing technology, miniaturization of electrical devices, and development of algorithms that were key in making the closed-loop system possible. The next major advancement will be a completely implantable closed-loop system to manage diabetes.


Closed-loop drug delivery promises autonomous control of pharmacotherapy through the continuous monitoring of biomarker levels. This level of precision medicine and polypharmacy is an active area of research and offers many exciting possibilities in the future. BioMEMS offer possibilities to miniaturize biosensors, enabling them to be incorporated with drug-delivery devices with extremely small footprint that minimize both power consumption and implantation trauma. MEMS fabrication also allows mass production [that] can be easily scaled without sacrificing its high reproducibility and reliability, allowing seamless integration with control circuitry and telemetry. By integrating these systems with drug-delivery devices, which can also be MEMS-based, closed-loop drug-delivery can be achieved.


MD+DI: In your personal opinion, what are some of the more significant challenges that stand in the way of progress when it comes to advancing drug-delivery systems? How do you think we can begin to address some of these challenges?


Vyakarnam: While new technological developments are exciting, proving clinical efficacy with superior results over standard of care can be expensive and time consuming. In the case of implantable drug delivery systems, compelling evidence needs to be generated that slow or reverse disease progression as a result of localized drug-delivery compared to the standard oral and parenteral routes of administration. These issues need to be addressed at the time of clinical trial design itself. Improvement in patient compliance and convenience need to be coupled with tangible clinical endpoints to justify reimbursement from a healthcare economics standpoint – making the new development commercially attractive.


Integration of several technologies from MEMS to biosensors to drug formulations is not trivial and requires a multi-disciplinary systems approach in fabricating the implantable drug-delivery systems for reliability and quality. On top of that the medical field is risk averse in adopting new technologies as patient safety is paramount. A careful selection and integration of time-tested technologies and materials from a biostability and biocompatibility standpoint will accelerate clinical translation and bring new products in the market place sooner.


MD+DI: Finally, what does the future look like for drug-delivery systems that can deliver drugs to the eye? What are the challenges involved, and what are some of the more recent novel developments pushing this field of research further?


Vyakarnam: By 2030 nearly 20 million in the United States will have vision loss or low vision if left untreated due to age-related conditions like macular degeneration (AMD), glaucoma, and diabetic retinopathy. Despite breakthroughs in drugs to treat these chronic conditions, they do not realize their full potential as they rely on very inefficient eye drops or intravitreal injections that are highly burdensome to patients resulting in poor compliance. In many ways [the] eye is an anatomically insular organ where localized drug delivery is the preferred route of administration to be efficacious, which makes a compelling case for developing implantable drug-delivery systems.


Miniaturized sustained drug-delivery implants are very promising to treat chronic ocular conditions and several are in development. Recently, FDA approved Yutiq (EyePoint) for the treatment of chronic non-infectious uveitis using a corticosteroid affecting the posterior segment of the eye. Yutiq is a non-bioerodible intravitreal drug-delivery implant that delivers fluocinolone acetonide for 36 months. While sustained delivery of small-molecule therapeutics seems to be in the realm of possibility, sustained delivery of Anti-VEGF biologics for AMD is still very challenging. Maintaining stability of these biologic therapeutics under physiologic conditions is not trivial, and several approaches are in development. In the case of AMD treatment, the goal is to reduce the frequency of intravitreal injections from the current 6–12 times a year to 2–3 times a year to ease patient burden. Bioresorbable drug-delivery implants that can also provide zero-order sustained drug delivery will offer a big advantage in the long-term disease management of glaucoma and AMD. Combining diagnostic sensing, like intraocular pressure, with drug delivery in a closed-loop system can be very appealing in the treatment of glaucoma to slow down its progression.