Solutions to Advance Drug Development

The most complex step of developing a therapeutic is to design its appropriate delivery system. Developing effective, non-harmful, long-lasting drug delivery systems is a major barrier facing the pharmaceutical industry because finding an effective, novel therapeutic is only half of the battle. The drug must then find its way to the active site and be bioavailable to treat the condition for which it was selected.

With the help of new organ-on-a-chip (OOC) models, a solution to this dilemma may be on the horizon, and along with it, improved pharmaceutical options for a variety of ailments.

OOCs could address shortcomings in the current drug discovery pipeline

Historically, drug delivery and formulation research has depended on cell lines or animal models.¹ Neither of these approaches are fully accurate when it comes to translating the results to humans. Animals used for research have vastly different physiology from humans, making the results from these studies indirectly translatable to human clinical research at best. They also come with a host of ethical conundrums—they must be housed and treated in compliance with ethics regulations governing research animals and are expensive to attain and maintain.

In contrast, 2D cell lines are inexpensive and easy to use, but they lack the complexity and species specificity for translatability. For example, results attained may or may not translate to subsequent animal and human clinical trials further down the pipeline. This also brings about the question of which candidates are missed because the current pipeline of 2D cell models-to-animal models-to human clinical trials eliminated them before their effect was identified. These shortcomings can increase the resource commitment required for drug formulation and delivery studies, lengthening the overall process from discovery to approval, and may cause novel therapeutic failure during preliminary testing.

OOC models can replace both animal and cell line research. By building a 3D scaffold onto a chip, this model more accurately mimics a human organ system, including all interwoven construction of the cells and spaces between them. OOC models are more accurate, can be used at a fraction of the cost of past cell and animal models, and require none of the ethics of animal experimentation.

The requirement for accurate models that represent human systems is further complicated by how pharmaceutical drugs must be delivered to their active site. The therapeutic must also be able to reach the active site, be dissolved or absorbed efficiently, and still maintain its effective treatment potential. OOC models are a relatively new technology that can be used to study and solve this complex problem.

The construction of OOC models

OOC models bring the technology of 3D printing to the pharmaceutical research field using a method called bioprinting. Bioprinting is performed using bioink, a soft biomaterial printed together with living cells. Several different biomaterials are available to use for bioink, including gelatin, alginate, agar, agarose, collagen, chitosan, and silk.² OOC models can be used for mechanistic studies and proof-of-concept drug testing.

The complex channels formed in OOC models replicate the architecture of tissues and organs, but controlling the properties and structure of the soft scaffolds that make up the OOC model is complex. The full model typically includes the soft scaffold of cells surrounded by an incubator regulating the oxygen, carbon dioxide, and temperature of the model as well as pumps and mechanical activators to generate the overall system. OOC models are very sensitive to their environment, which makes the right setup of controls and environmental parameters essential. Choosing the right materials for the OOC to be placed on and housed within depends on the needs of each experiment and must be tailored to the application.

The requirement for accurate models that represent human systems is further complicated by how pharmaceutical drugs must be delivered to their active site.

Applying OOCs to research questions in the lab

The process of finding compound formulations that maintain their effectiveness despite the previously mentioned challenges is almost entirely trial and error, according to Rebecca Carrier, PhD, principal investigator at the Advanced Drug Delivery Research Lab at Northeastern University.³ The lab is using OOC models for their drug delivery, efficacy, and formulation testing.

As Carrier told Lab Manager in an exclusive interview, “Currently, formulation design is more of an art than a science, based largely on precedence and familiarity rather than true understanding of how design will impact performance. As she explains, formulations are screened using in vitro tests, such as testing of drug solubility in a given formulation or the ability of a given formulation to stabilize a supersaturated drug solution.

“The translation of these routinely conducted in vitro tests to in vivo results are at best unclear and at worst misleading,” adds Carrier. “To improve the situation, two things are needed. One is better in vitro tests and models capturing essential components of in vivo biology and physiology, and the other is computational frameworks that enable translation of in vitro results to predictions of in vivo performance.”

The acidic environment of a human stomach can also inactivate and destroy many pharmaceutical drugs before they even have a chance to reach their active site. Oral therapeutics are more desirable than injections because the pain and fear associated with syringes may reduce compliance and willingness to take the therapeutic routinely. Carrier’s group uses OOCs to gain insights into bioavailability and to answer major biological questions about how drug formulation impacts its delivery. Using OOCs to simulate the intestinal environment in the presence of lipids—like Carrier’s research group is doing—and observe the effect of this environment on drug bioavailability, dissolution, and partitioning presents a major step forward, reducing the need for problematic animal and cell models.³

In addition to this work, OOCs enable the study of inflammatory conditions in the GI tract using patient-derived or commercially available cells. This can help to determine how different food substances affect the GI tract, offering answers to questions about appropriate nutritional interventions.³ Both research projects would previously have only been possible using animal models but are now successfully being investigated using OOCs.³

“The gut-on-a-chip model we work with in our lab enables facile visualization and analysis of the intestinal mucosa interface. This barrier, including intestinal mucus as well as epithelial barriers, is highly significant in absorption of compounds from the gut and interactions with the microbiome. Our system enables in-depth characterization and analysis of this interface using standard microscopy and image analysis as well as biochemical analysis,” explains Carrier.

Donald Ingber, MD, PhD, is the founding director of the Wyss Institute, which has been developing and characterizing OOC models since 2007. As Ingber states on the institute’s website, “We took a game-changing advance in microengineering made in our academic lab … and turned it into a technology that is now poised to have a major impact on our society.”⁴

The Wyss Institute has developed OOCs that have been installed in more than 150 labs, and were used by the FDA to study the safety of COVID-19 therapeutics. Their OOC models have also been used to conduct research on influenza, malnutrition, radiation exposure, and cystic fibrosis.⁴

The future looks bright for bioprinting

Bioprinting OOCs provides an excellent alternative to traditional 2D cell line and animal model experiments. Using OOCs can reduce the need for inaccurate models, which can mistakenly identify drug candidates whose effects are not translatable to humans. OOCs reduce the need for expensive, time-consuming, and ethically designed animal experiments. The system can be generated to model specific systems such as the eye or intestinal tract, yielding environment-specific answers that may not have been achievable using past techniques.

Technique	How it Works	Pros/Cons
Inkjet bioprinting	Uses a piezoelectric actuator to generate acoustic waves through the bioink chamber that will become the OOC.² The voltage pulse generates droplets when applied between a pressure plate and an electrode.²	Compatible with living materials Low cost and time-efficient
Extrusion-based bioprinting	Uses pneumatic force or mechanical force. A dispenser system on a robotic stage is controlled to deposit bioinks on a substrate, which are then driven into the materials by screw-driven, piston-driven, or air pressure force.²	Can be executed with many different materials and can perform high-cell density deposition
Laser-assisted bioprinting	Adapted and applied to bioprint nucleic acids including DNA and organ cells. This technique can print biomaterials with high resolution by using a pulsed laser beam on a donor slide to generate the OOC.²	Although optimized for delivery of nucleic acids, the presence of the lasers can increase cell mortality
Vay polymerization	Relies on a combination of polymeric solutions and a laser-solidification mechanism.² By shining the UV source through the mirror and subsequent lens (similar to a microscope setup), crosslinked or photopolymer bioink can be inserted into the material below to create an OOC.²	Low cost and time-efficient Comes with risk of damage caused by UV light to cell DNA⁵

The future is bright for bioprinting and drug delivery as researchers around the world continue to refine their OOCs and related methodology, and we continue to learn more about systems that have, until now, remained out of experimental reach. Will the future of pharmaceutical drug formulation and delivery studies be able to use fewer animal and cell models and instead be designed based on human 3D models that accurately represent our physiology? OOCs may make this future a reality.

References:

1. Khalil, A., Jaenisch, R., Mooney, D. “Engineered tissues and strategies to overcome challenges in drug development.” Advanced Drug Delivery Reviews, 2020 158, 116-139. DOI: https://doi.org/10.1016/j.addr.2020.09.012

2. “An overview on materials and techniques in 3D bioprinting toward biomedical application.” Engineered Regeneration, 2021, 2, 1-8. DOI: https://doi.org/10.1016/j.engreg.2020.12.001

3. “‘Gut lab’ helps scientists understanding the effects foods have on our bodies and improve drug development.” Northeastern Global News. April 13 2023. https://news.northeastern.edu/2023/04/13/drug-delivery-research/ 

4. “Human Organs-on-Chips.” Wyss Institute. Harvard Edu. 2023. https://wyss.harvard.edu/technology/human-organs-on-chips/#

5. "Development and implementation of a significantly low-cost 3D bioprinter using recycled scrap material." Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Technologies-applied-to-3D-bioprinting-generalpros-and-cons_tbl2_370222262. Accessed 29 Aug 2023.