Rheolution Article | May 2021
On the importance of mechanical behavior of hydrogel-based drug delivery systems
by Dr. Dimitria Bonizol Camasao
Senior Application Specialist, Rheolution Inc.
When we take a small pill for headache or muscular pain, the drug makes a large tour in our body and acts for a short period of time. Starting in the mouth, it will travel through the esophagus, stomach and intestine. In the digestive system, the pill will be immersed in digestive fluids where it will start to be degraded and absorbed into the bloodstream. Once in the blood, the drug can travel through the whole body. The drug’s role is to prevent injured cells from releasing specific chemical compounds. These chemical compounds are responsible for sending a pain message to the brain through the nervous system. Therefore, the drug can stop the pain by preventing the release of these chemicals. This process can take from a couple of minutes to a few hours. Since the drug is quickly available after digestion and susceptible to elimination by the body, repeated administration is often required to relieve pain or to achieve the desired therapeutic effect.
Although oral dosing of drugs is the most popular route of administration due to its convenience and relative low cost, drug absorption can be affected by a number of factors including age, diseases, stress, body mass index, concomitant food and gastrointestinal pH . Other types of routes such as injection (intravenous), transdermal (topical), inhalation and rectal routes are less affected by these factors. However, for all of them, the drug concentration in the blood reaches its maximum (and minimum) level in a relatively short time frame and therefore its full therapeutic potential is minimized. To overcome possible absorption deficiencies, off-target effects and short drug availability, controlled drug delivery systems (CDDS) composed of a polymeric matrix containing the therapeutic agent have been investigated in the last decades.
Controlled drug delivery systems (CDDS)
The idea of CDDS is to entrap the drug in a polymeric matrix and release it at a controlled rate for an extended period of time in the desired site. Hydrogels formed by a network of polymers and a large amount of water (70-99%) are popular candidates for composing these systems. Hydrogel-based drug delivery systems (DDS) show physical similarity to human tissues due to their composition, good biocompatibility, and easy encapsulation of hydrophilic drugs.
Hydrogel-based DDS can be classified based on their size: macrogels, microgels and nanogels. They can be surgically implanted in the body, placed in contact with the skin or administered via oral, pulmonary or systemic routes. A successful example of implanted DDS is the Infuse™ Bone Graft composed of type I collagen gel and recombinant human bone morphogenetic protein 2 (BMP2), known for inducing bone formation. Wound dressings with transdermal drug delivery are an example of macrogels placed in contact with the skin for controlled release of therapeutic agents to promote wound healing .
The drug release mechanisms can be related to the diffusion of the drug from the matrix, chemical degradation or swelling of the matrix, or a specific stimulus from the target tissue , illustrated in the image below. Therefore, the physicochemical and viscoelastic properties of the hydrogels should be well known for an optimal design of an effective DDS.
Promising alternatives for cancer treatment
A very exciting application of DDS is in cancer treatment. Nanogels have been widely investigated to deliver therapeutic agents specifically to solid tumors to improve efficacy and reduce the severe adverse side effects of cancer treatments. Their mechanical properties were shown to influence the circulation time of the nanoparticles in the blood, their spatiotemporal distribution, tumor penetration and interaction with cancer cells. Soft nanoparticles were shown to persist longer in the vasculature than stiffer counterparts. In accordance, stiffer nanoparticles were found to have superior retention in the spleen compared to soft nanoparticles. This difference was attributed to the ability of soft nanoparticles to squeeze through barriers of the vasculature (including spleen, liver) and remain longer in the blood circulation compared to the low deformable stiff nanoparticles. Therefore, decreasing nanoparticle elasticity was already suggested to reduce their blood clearance and improve their tumor targeting. Soft nanoparticles were also found to achieve a higher penetration depth in tumors .
Overall, the mechanical properties play an important role in different steps of the DDS development and application. The release of the drug can be correlated with the progressive degradation of the polymeric matrix within the body. Tuning the initial mechanical properties and the stability of the matrix can be used to achieve optimal rates of drug release. In the case of nanoparticles, their stiffness can affect their blood availability, tumor targeting and penetration.
A number of DDS are already applied in clinics and the advancements in biomaterials and their characterization tools have broadened the field even more. With the increasing biomaterials systems and target applications, the impact of this technology is likely to increase in the coming years: further changing the scale, efficacy and cost of therapeutics, and improving human health care.
 Abuhelwa, A. Y., Williams, D. B., Upton, R. N., & Foster, D. J. (2017). Food, gastrointestinal pH, and models of oral drug absorption. European journal of pharmaceutics and biopharmaceutics, 112, 234-248.
 Abu-Thabit, N. Y., & Makhlouf, A. S. H. (2018). Historical development of drug delivery systems: From conventional macroscale to controlled, targeted, and responsive nanoscale systems. In Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications, Volume 1 (pp. 3-41). Woodhead Publishing.
 Li, J., & Mooney, D. J. (2016). Designing hydrogels for controlled drug delivery. Nature Reviews Materials, 1(12), 1-17.
 Hui, Y., Yi, X., Hou, F., Wibowo, D., Zhang, F., Zhao, D., … & Zhao, C. X. (2019). Role of nanoparticle mechanical properties in cancer drug delivery. ACS nano, 13(7), 7410-7424.