Ultrasound-triggered drug delivery using stimuli-responsive hydrogels

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Ultrasound-triggered drug delivery using stimuli-responsive hydrogels refers to the process of using ultrasound energy for inducing drug release from hydrogels that are sensitive to acoustic stimuli. This method of approach is one of many stimuli-responsive drug delivery-based systems that has gained traction in recent years due to its demonstration of localization and specificity of disease treatment. Although recent developments in this field highlight its potential in treating certain diseases such as COVID-19, there remain many major challenges that need to be addressed and overcome before more related biomedical applications are clinically translated into standard of care.

Contents

Types of Hydrogels Used in Drug Delivery Systems

Traditional Hydrogels

Figure 1.0 - Synthesis process of nanocomposite hydrogels NC Gel synthesis figure.png
Figure 1.0 – Synthesis process of nanocomposite hydrogels

Hydrogels are three dimensional structures consisting of hydrophilic polymers (i.e., polymers, colloids, etc.) that form networks through cross-linking processes. The macromolecules involved in the formation of hydrogels are able to absorb and retain large amounts of water and other aqueous substances. Since its discovery in 1960, [1] hydrogels have become a crucial component in biomedical research and applications. A few examples of hydrogel use include organ regeneration, [2] wound healing, [3] [4] [5] and drug delivery. [6] [7] Hydrogels are generally classified based on the following characteristics: material, crosslinking mechanism, physical structure, electric charge, and response to stimuli. [8] Synthesis of hydrogels are developed from a combination or isolated forms of natural and synthetic polymers. [2] [9] The main examples of natural polymers used to derive hydrogels include polysaccharides, [9] polypeptides, [10] and polynucleotides. [5] Several known examples of synthetic polymeric constituents include poly (vinyl alcohol) (PVA), [7] [9] [11] poly (acrylic acid) (PAA), [7] [9] [11] and poly (2-hydroxyethyl methacrylate) (PHEMA). [9] [11] [12] [13] The crosslinking mechanism of the hydrophilic macromolecules are driven by covalent bonding, resulting in a physical- or chemical-type hydrogel. Physical hydrogels contain reversible matrices of hydrogen and non-covalent bonds, while chemical hydrogels are composed of irreversible matrices that are molecularly held together by covalent bonds. Used as another parameter in characterizing gels, electric charge (also referred to as ionic character) describes the ability of the macromolecules to drive swelling behavior. Hydrogels classified based on this property fall under three main categories: cationic, anionic, and amphoteric. Bawa et al. demonstrated that cationic gels swell in acidic environments but remain condensed in basic environments. [14]

Smart Hydrogel Polymers

Figure 2.0 - Various examples of stimuli inducing drug release from loaded-smart hydrogels Figure 2.0.png
Figure 2.0 - Various examples of stimuli inducing drug release from loaded-smart hydrogels

Since traditional hydrogels were able to encapsulate and carry materials, research into drug-loaded hydrogels began to expand in the field of drug delivery. Dubbed as “smart hydrogels” or “stimuli-responsive hydrogels”, these gels are able to dynamically respond to external or internal stimuli in addition to possessing similar swelling-deswelling properties of traditional hydrogels. Various examples of external stimuli that have been used to control smart hydrogels in drug delivery systems include temperature, [10] [12] [13] [15] [16] [17] pH, [12] [13] [15] [16] [17] light, [10] [12] [15] [16] ultrasound, [15] [16] and enzymes. [18] Additional considerations in designing smart hydrogels involve fundamental understanding of bond strength, molecular weight, degree of polymerization, polymer structure, and molecular assembly. [17] [19] The bond strength describes the cross-linking strength of the hydrogel, which is considered in designing drug release mechanisms of hydrogel-based platforms. Scientific understanding of the molecular weight of gels is taken into account when loading drugs of increasing weight. [20] Similar to conventional hydrogels, the polymeric chain (or backbone) of the smart hydrogels is derived from polysaccharides, polypeptides, and polynucleotides. Examples of natural polymers include alginate, [21] [22] [23] chitosan, [6] [17] [24] [25] cellulose, [6] [13] gelatin, [13] fibrin, [17] and collagen. [26] Hydrogel size and type are the two main properties considered in designing hydrogels when seeking the optimal delivery route for drug administration. [27] Various examples of hydrogel type designs include nanoparticles, [13] [28] nanogels, [16] [28] [29] and microgels. [29] For example, El-Sherbiny et al. proposed gelatin-based hydrogel nanoparticles that were stimulated by magnetic forces. [30] Other variables considered in hydrogel design include safety, biodegradability, [31] drug loading capacity, and on-demand control of drug release [23]. The main safety concerns in formulating hydrogels include bacterial infection [32] and biocompatibility. [26] The final parameter considered in developing hydrogels for drug delivery systems revolve around the embedded payload within the hydrogel. [33] Cells, proteins, and therapeutic drugs are the main payloads used in hydrogel-based drug delivery platforms. [34] In one example of payload use, Jiang et al. demonstrated the stimulated release of gallic acid from chitin-based hydrogel via ultrasound induction. [24]

Use of Ultrasound for Drug Therapy

General Overview of Ultrasound

According to the Moyano et al., ultrasound refers to vibrational mechanical waves with frequencies greater than 20 kilohertz (kHz). [35] Ultrasound is traditionally used for imaging, monitoring, and diagnosing a broad range of conditions in the medical field. Various examples of ultrasound modalities include Doppler ultrasound, focused ultrasound, and echocardiography. The key component of using most ultrasound devices is a transducer that consists of an array of piezoelectric crystals. The atoms within these crystals vibrate under electrical current stimulation, converting this electrical energy into mechanical, in this case, high acoustic or ultrasonic energy. When the sonicating transducer is directed at the human body, the resulting sound pressure waves produced by the transducer will pass through the dermal layer and reach the tissue where the waves are reflected (or echoed) back to the transducer and converted back into electrical signals for image reconstruction. Tissue characteristics such as density affect the intensity of the reflected sound waves. Other parameters such as beam frequency, equipment components, and imaging settings contribute towards the resolution of the ultrasound application. Ultrasound has also been used for therapeutic purposes because it is non-invasiveness, able to provide deeper tissue penetration, and safely localize application of acoustic energy. [19]

Figure 3.0 - Example of ultrasound machine and different types of associated transducers UsMachTxPhoto.jpg
Figure 3.0 - Example of ultrasound machine and different types of associated transducers

While ultrasound modalities are generally considered safe, extreme levels of human exposure to ultrasound can increase injury risk. [35] In the US, the Food and Drug Administration (FDA) guidelines, [34] the maximum allowed exposure to ultrasound for use is defined by the following key parameters: mechanical index, [36] thermal index, [37] spatial-peak temporal-peak intensity, [38] spatial-peak pulse-average power, [39] and spatial-peak temporal-average power. [34] Mechanical index (MI) is a unitless metric that is used to measure the acoustic power output from ultrasound use. Since the MI is inversely proportional to the ultrasonic beam frequency, the MI will be lower at higher frequencies. The thermal index (TI) describes the risk of increasing the temperature of the tissue being sonicated by ultrasound. A solution to decreasing TI involves the reduction of the time that the sonicating transducer is focused on the targeted area. [37] The spatial-peak temporal-peak (SPTP) power refers to the highest intensity output of the ultrasound beam during implementation. The spatial-peak pulse-average (SPPA) power is a measure of the maximum intensity output averaged over the duration of ultrasound use in. The spatial-peak temporal-average power describes the measure of the highest intensity output generated by the repeating pulse of the ultrasound beam over a period of time.

Effects of Focused Ultrasound on Smart Hydrogels

Due to the sonication capability of ultrasound and drug-release property of smart hydrogels, there has been scientific interest in controlling the release of the payload from hydrogels. [10] Focusing and directing acoustic energy (that can convert to thermal or mechanical energy [36] [40] ) towards smart hydrogels, implanted within tissue at times, induces a hydrogel response that results in the release of the embedded payload. Although hydrogels that are sensitive to mechanical pressure are generally used in ultrasound-triggered drug delivery platforms, hydrogels that respond to changes in temperature have also been used for these systems. [10]  For example, Makhmalzadeh et al. proposed an ultrasound-triggered drug delivery method involving the use of thermo-responsive hydrogels loaded with silibinin, a cancer drug for treating melanoma. [16] [41] At low temperatures, these thermo-responsive hydrogels exist in liquid form but following ultrasonication, they transition into a gel state. [16] [25] Although ultrasound- and thermo-sensitive hydrogels are responsive to certain ultrasound modalities, they differ in how they respond to external stimuli. Ultrasound-responsive hydrogels are capable of being stimulated by more than one type of stimulation force through ultrasound. [42] Conversely, thermo-responsive hydrogels, as the name specifies, can only respond to the thermal forces induced by ultrasound. [13] Despite this, thermo-responsive hydrogels have been widely used in cancer-based drug delivery systems. [6]

Figure 4.0 - Activation of ultrasound disrupts hydrogel matrix and allows for drug release. Turning off ultrasound allows for hydrogel to restore its matrix Figure 3.0.png
Figure 4.0 - Activation of ultrasound disrupts hydrogel matrix and allows for drug release. Turning off ultrasound allows for hydrogel to restore its matrix

Of the existing ultrasound modalities, focused ultrasound has been used extensively in drug delivery research. [33] [34] High-Intensity Focused Ultrasound (HIFU) and Low-Intensity Focused Ultrasound are the two main techniques used in inducing drug release from smart hydrogels. [43] Current HIFU applications are used for ablating tumors located at increased depths. [44] Since HIFU is able to invoke high temperatures, they have been used for cancer therapy by stimulating drug release from smart hydrogels via thermolysis mechanisms. [45] In regard to the use of ultrasound- and thermo-responsive hydrogels for drug delivery, HIFU is able to stimulate both types of hydrogels. [45] In one study related to cancer therapy, HIFU exhibited high efficiency inducing nanovaccine release from hydrogel-based carriers. [46] Although HIFU has been studied in various capacities, this technique can cause irreparable damage to healthy tissue. [31] Therefore, LIFU has been the conventional method for use in hydrogel responsive drug delivery platforms. In other areas of the biomedical field, LIFU has been used for stimulation such as bone regeneration in tissue engineering applications. [47] [48] Due to its lower generated acoustic power output, LIFU is preferred over HIFU in biomedical applications involving neuromodulation [49] and other brain-related procedures. [50] Studies have shown that LIFU has proven to be a cost-effective and non-invasive method for hydrogel-based drug delivery. [51]

The underlying drug-releasing mechanism induced by focused ultrasound onto ultrasound-sensitive hydrogels is based on mechanical or thermal effects. [19] [31] [45] Mechanical-based ultrasound sonication mechanisms refer to the conversion of acoustic energy into mechanical energy with various types that include acoustic cavitation force, [31] [45] or oscillation force. [36] Generally, applying mechanical pressure to a responsive hydrogel loaded with drugs causes the hydrogel to deform. This deformation reduces the structural integrity of the hydrophobic core, allowing for the release of the drug payload. [43] Both ultrasound- and thermo- responsive hydrogels are capable of carrying various embedded carriers of drug payloads which include metal-organic framework, [52] nanoparticles, [23] [28] and liposomes. [53] Although many studies have demonstrated the irreversible compression of hydrogels induced under ultrasound, Goncalves et al. designed hydrogel-based nanoparticles that were capable of “self-healing”, meaning they were able to return to their original form following drug release from its depot. [28]

Acoustic cavitation forces, specifically, have been used in conjunction with ultrasound-responsive hydrogels for drug delivery. This type of mechanical force refers to the formation, growth, and destruction of bubble occurs that results in the generation of acoustic energy. There are varying degrees of cavitation which divided into three groups: sonoporation, [15] stable cavitation, [3] [15] [36] and inertial cavitation. [19] [36] Sonoporation refers to the process of using ultrasound to open pores (or permeability) of cellular membranes to allow substances of interest to enter into the targeted cell. In cases where microbubbles are coated with hydrogels, these embedded carrier systems undergo stable cavitation and inertial cavitation. [36] Stable cavitation characterizes vapor bubbles that oscillate within its own equilibrium, while inertial cavitation describes bubbles that generate a net growth each time the bubble expands and results in the bubble collapsing violently. Severe cavitation increases the risk of damage to tissue and drug degradation. [3] [7] Other forces generated by ultrasound that is used in several hydrogel-based platforms are hyperthermia [36] [45] and radiation. [36] These forces are generally created by HIFU as they generate high levels of heat. Thus, guidelines established by the FDA help ensure the safe use of ultrasound in all biomedical applications, inclusive of drug delivery systems, based on the scientific understanding of these mechanical forces.

Drug delivery applications and effects

Tissue engineering

In regard to tissues, ultrasound is generally used for imaging and monitoring tissue pathologies. [34] Due to its ability to penetrate through tissue easily, [25] ultrasound has been widely studied and developed for drug delivery applications in the field of tissue engineering. In order for hydrogels to release drugs at the targeted location, they must be injected or implanted within the tissue. Injection of hydrogels is usually preferred over implantation due to its minimal invasiveness, [2] [6] [25] reduced healing time following the procedure, [47] and biocompatibility. [54] In one study, Liu et al. proposed a novel design of injectable chemotaxis hydrogels to help promote the migration of bone marrow mesenchymal cells for cartilage repair. [55] Other examples of using smart hydrogels and ultrasound in tissue engineering applications include cartilage repair, [55] bone repair, [47] [56] and wound healing. [3] The design of these drug delivery platforms is specific to each tissue type and its intended use. [26]

Cancer treatment

In the field of cancer, ultrasound is commonly used for helping health care professionals detect and develop a diagnosis in affected patients. [34] In the context of drug delivery, ultrasound has been used for a wide variety of therapeutic applications which include but are not limited to melanoma, [16] ovarian cancer, [7] [16] and breast cancer. [16] [21] Hydrogels are generally used in designing these drug delivery platforms due to minimal invasiveness (if injected) and its ability to carry a different cancer drugs. These hydrogel-based systems are also paired with chemotherapy treatments. [45] Cancer drugs used in this drug delivery platforms include doxorubicin, [6] [21] [40] mitoxantrone, [22] paclitaxel, [16] [57] silibinin, [16] [57] and cisplatin. [16] [57] In a cancer therapy study, Baghbani et al. proposed a method of pairing ultrasound with doxorubicin-loaded alginate-stabilized perfluorohexane (PFH) nanodroplets. [21]

Gene therapy

Although it is generally used in combination with cancer therapeutic treatments, [16] gene therapy has become a topic of interest in the drug delivery field. Gene therapy refers to the insertion of genes into a biological system in an attempt to add or modify mutated genes for therapeutic benefit. In order to attain high transgene expression, the electrostatic interaction between the gene and hydrogel polymer and the controlled release of the drug payload from the hydrogel is necessary. [36] Several gene therapy drugs used in hydrogel-based drug delivery systems include CRISPR/Cas9, [58] siRNA, [40] [59] and other RNA-based drugs. [59] In a gene therapy study, Han et al. proposed a focused ultrasound-responsive hydrogel-based system for delivering siRNA nanoparticles to the targeted tumor site [60]

Challenges and future development

The main challenge for future ultrasound-triggered hydrogel responsive delivery systems is to develop safer guidelines for using HIFU to take advantage of its benefits. In doing so, this will lead to improvements on FDA guidelines for ultrasound use. Therefore, the use of LIFU or lower acoustic energy intensity settings is suggested as the conventional method for decreasing injury risk, specifically damage to healthy tissue, until then. [34] Focused ultrasound continues to be the primary type of ultrasound technique used in drug delivery systems. Another challenge presented in using ultrasound for inducing drug release from smart hydrogels in delivery platforms is inappropriate drug administration and unexpected complications. [31] Currently, on-demand drug release from ultrasound-responsive hydrogels is still difficult to fully control when only using ultrasound. Yeingst et al. suggested that future hydrogel-based delivery platforms will be designed based on the drug payload to optimize the interaction between the ultrasound and stimuli-responsive hydrogel. [34] Future development of drug delivery systems will continue to incorporate ultrasound and smart hydrogel designs.

Related Research Articles

<span class="mw-page-title-main">Soft matter</span> Subfield of condensed matter physics

Soft matter or soft condensed matter is a subfield of condensed matter comprising a variety of physical systems that are deformed or structurally altered by thermal or mechanical stress of the magnitude of thermal fluctuations. These materials share an important common feature in that predominant physical behaviors occur at an energy scale comparable with room temperature thermal energy, and that entropy is considered the dominant factor. At these temperatures, quantum aspects are generally unimportant. Soft materials include liquids, colloids, polymers, foams, gels, granular materials, liquid crystals, flesh, and a number of biomaterials. When soft materials interact favorably with surfaces, they become squashed without an external compressive force. Pierre-Gilles de Gennes, who has been called the "founding father of soft matter," received the Nobel Prize in Physics in 1991 for discovering that methods developed for studying order phenomena in simple systems can be generalized to the more complex cases found in soft matter, in particular, to the behaviors of liquid crystals and polymers.

<span class="mw-page-title-main">Hydrogel</span> Soft water-rich polymer gel

A hydrogel is a biphasic material, a mixture of porous, permeable solids and at least 10% by weight or volume of interstitial fluid composed completely or mainly by water. In hydrogels the porous permeable solid is a water insoluble three dimensional network of natural or synthetic polymers and a fluid, having absorbed a large amount of water or biological fluids. These properties underpin several applications, especially in the biomedical area. Many hydrogels are synthetic, but some are derived from nature. The term 'hydrogel' was coined in 1894.

<span class="mw-page-title-main">Focused ultrasound</span> Non-invasive therapeutic technique

High-intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that uses non-ionizing ultrasonic waves to heat or ablate tissue. HIFU can be used to increase the flow of blood or lymph or to destroy tissue, such as tumors, via thermal and mechanical mechanisms. Given the prevalence and relatively low cost of ultrasound generation mechanisms, the premise of HIFU is that it is expected to be a non-invasive and low-cost therapy that can at least outperform care in the operating room.

Therapeutic ultrasound refers generally to any type of ultrasonic procedure that uses ultrasound for therapeutic benefit. Physiotherapeutic ultrasound was introduced into clinical practice in the 1950s, with lithotripsy introduced in the 1980s. Others are at various stages in transitioning from research to clinical use: HIFU, targeted ultrasound drug delivery, trans-dermal ultrasound drug delivery, ultrasound hemostasis, cancer therapy, and ultrasound assisted thrombolysis It may use focused ultrasound or unfocused ultrasound.

<span class="mw-page-title-main">Phonophoresis</span>

Phonophoresis, also known as sonophoresis, is the method of using ultrasound waves to increase skin permeability in order to improve the effectiveness of transdermal drug delivery. This method intersects drug delivery and ultrasound therapy. By assisting transdermal drug delivery, phonophoresis can be a painless treatment and an alternative to a needle.

Poly(N-isopropylacrylamide) (variously abbreviated PNIPA, PNIPAM, PNIPAAm, NIPA, PNIPAA or PNIPAm) is a temperature-responsive polymer that was first synthesized in the 1950s. It can be synthesized from N-isopropylacrylamide which is commercially available. It is synthesized via free-radical polymerization and is readily functionalized making it useful in a variety of applications.

<span class="mw-page-title-main">Sonoporation</span> Technique in molecular biology

Sonoporation, or cellular sonication, is the use of sound in the ultrasonic range for increasing the permeability of the cell plasma membrane. This technique is usually used in molecular biology and non-viral gene therapy in order to allow uptake of large molecules such as DNA into the cell, in a cell disruption process called transfection or transformation. Sonoporation employs the acoustic cavitation of microbubbles to enhance delivery of these large molecules. The exact mechanism of sonoporation-mediated membrane translocation remains unclear, with a few different hypotheses currently being explored.

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body. 

Smart polymers, stimuli-responsive polymers or functional polymers are high-performance polymers that change according to the environment they are in.

Microbubbles are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, medicine, life science, and food technology. The composition of the bubble shell and filling material determine important design features such as buoyancy, crush strength, thermal conductivity, and acoustic properties.

<span class="mw-page-title-main">Sonodynamic therapy</span>

Sonodynamic therapy (SDT) is a noninvasive treatment, often used for tumor irradiation, that utilizes a sonosensitizer and the deep penetration of ultrasound to treat lesions of varying depths by reducing target cell number and preventing future tumor growth. Many existing cancer treatment strategies cause systemic toxicity or cannot penetrate tissue deep enough to reach the entire tumor; however, emerging ultrasound stimulated therapies could offer an alternative to these treatments with their increased efficiency, greater penetration depth, and reduced side effects. Sonodynamic therapy could be used to treat cancers and other diseases, such as atherosclerosis, and diminish the risk associated with other treatment strategies since it induces cytotoxic effects only when externally stimulated by ultrasound and only at the cancerous region, as opposed to the systemic administration of chemotherapy drugs.

Hydrogels are three-dimensional networks consisting of chemically or physically cross-linked hydrophilic polymers. The insoluble hydrophilic structures absorb polar wound exudates and allow oxygen diffusion at the wound bed to accelerate healing. Hydrogel dressings can be designed to prevent bacterial infection, retain moisture, promote optimum adhesion to tissues, and satisfy the basic requirements of biocompatibility. Hydrogel dressings can also be designed to respond to changes in the microenvironment at the wound bed. Hydrogel dressings should promote an appropriate microenvironment for angiogenesis, recruitment of fibroblasts, and cellular proliferation.

<span class="mw-page-title-main">Dextran drug delivery systems</span> Polymeric drug carrier

Dextran drug delivery systems involve the use of the natural glucose polymer dextran in applications as a prodrug, nanoparticle, microsphere, micelle, and hydrogel drug carrier in the field of targeted and controlled drug delivery. According to several in vitro and animal research studies, dextran carriers reduce off-site toxicity and improve local drug concentration at the target tissue site. This technology has significant implications as a potential strategy for delivering therapeutics to treat cancer, cardiovascular diseases, pulmonary diseases, bone diseases, liver diseases, colonic diseases, infections, and HIV.

<span class="mw-page-title-main">Focused ultrasound for intracranial drug delivery</span> Medical technique

Focused ultrasound for intracrainial drug delivery is a non-invasive technique that uses high-frequency sound waves to disrupt tight junctions in the blood–brain barrier (BBB), allowing for increased passage of therapeutics into the brain. The BBB normally blocks nearly 98% of drugs from accessing the central nervous system, so FUS has the potential to address a major challenge in intracranial drug delivery by providing targeted and reversible BBB disruption. Using FUS to enhance drug delivery to the brain could significantly improve patient outcomes for a variety of diseases including Alzheimer's disease, Parkinson's disease, and brain cancer.

Conventional drug delivery is limited by the inability to control dosing, target specific sites, and achieve targeted permeability. Traditional methods of delivering therapeutics to the body experience challenges in achieving and maintaining maximum therapeutic effect while avoiding the effects of drug toxicity. Many drugs that are delivered orally or parenterally do not include mechanisms for sustained release, and as a result they require higher and more frequent dosing to achieve any therapeutic effect for the patient. As a result, the field of drug delivery systems developed into a large focus area for pharmaceutical research to address these limitations and improve quality of care for patients. Within the broad field of drug delivery, the development of stimuli-responsive drug delivery systems has created the ability to tune drug delivery systems to achieve more controlled dosing and targeted specificity based on material response to exogenous and endogenous stimuli.

Pullulan bioconjugates are systems that use pullulan as a scaffold to attach biological materials to, such as drugs. These systems can be used to enhance the delivery of drugs to specific environments or the mechanism of delivery. These systems can be used in order to deliver drugs in response to stimuli, create a more controlled and sustained release, and provide a more targeted delivery of certain drugs.

<span class="mw-page-title-main">Reduction-sensitive nanoparticles</span> Drug delivery method

Reduction-sensitive nanoparticles (RSNP) consist of nanocarriers that are chemically responsive to reduction. Drug delivery systems using RSNP can be loaded with different drugs that are designed to be released within a concentrated reducing environment, such as the tumor-targeted microenvironment. Reduction-Sensitive Nanoparticles provide an efficient method of targeted drug delivery for the improved controlled release of medication within localized areas of the body.

pH-responsive tumor-targeted drug delivery is a specialized form of targeted drug delivery that utilizes nanoparticles to deliver therapeutic drugs directly to cancerous tumor tissue while minimizing its interaction with healthy tissue. Scientists have used drug delivery as a way to modify the pharmacokinetics and targeted action of a drug by combining it with various excipients, drug carriers, and medical devices. These drug delivery systems have been created to react to the pH environment of diseased or cancerous tissues, triggering structural and chemical changes within the drug delivery system. This form of targeted drug delivery is to localize drug delivery, prolongs the drug's effect, and protect the drug from being broken down or eliminated by the body before it reaches the tumor.

Bioprinting drug delivery is a method of using the three-dimensional printing of biomaterials through an additive manufacturing technique to develop drug delivery vehicles that are biocompatible tissue-specific hydrogels or implantable devices. 3D bioprinting uses printed cells and biological molecules to manufacture tissues, organs, or biological materials in a scaffold-free manner that mimics living human tissue to provide localized and tissue-specific drug delivery, allowing for targeted disease treatments with scalable and complex geometry.

Stretch-triggered drug delivery is a method of controlled drug delivery stimulated by mechanical forces. The most commonly used materials for stretch-triggered autonomous drug release systems are hydrogels and elastomers.

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