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Biosensor-Based Drug Delivery Systems: Innovations, Applications, and… 229
bio-recognition element of the sensor identifies the target analyte, while a transducer converts the result of the molecular recognition into an electrical signal. Different biomolecules such as enzymes, nucleic acids, antibodies, proteins, and peptides can be used as a bio-recognition element and biosensors can thus be used to detect specific physiochemical changes in the body (associated with the diseases) with high sensitivity and specificity. The performance of the biosensors can be optimized on the basis of selectivity, sensitiv­ity, linearity, response time, reproducibility and stability.
Biosensors can be integrated into drug delivery devices to provide feedback on drug levels and trigger drug release when needed. These systems can maintain therapeutic drug concentra­tions and avoid under- or over-dosing. For instance, biosensor­controlled insulin pumps can measure glucose levels and release insulin accordingly in diabetic patients [
1].
It is important to mention here that an in-depth knowledge of the physiology, pathophysiology of the disease, and pharmacody­namics and pharmacokinetics are sine qua non for development of biosensor-based drug formulations.

2.1 Types of Biosensors

Different types of biosensors featuring drug delivery systems have been developed with the ability to deliver drugs in response to biosensor readings. It is important here to know about the funda­mental structuring and classification of a biosensor based on its components and functioning.
The bioreceptors are considered as the primary component in biosensor construction. Based on the bioreceptor, biosensors are classified as enzymatic biosensors (most common biosensor class), immunosensors (possess high specificity and sensitivity and are specifically useful in diagnosis), aptamer or nucleic acid-based bio­sensors (possess high specificity for microbial strains and nucleic acid-containing analyte), and microbial or whole-cell biosensors.
The second classification is made on the basis of the transducer and sensors which are categorized as electrochemical (which is further grouped as potentiometric, amperometric, impedance, and conductometric), electronic biosensor, thermal biosensor, optical, and mass-based or gravimetric.
Some classifications are made depending on the detection sys­tem (optical, electrical, electronic, thermal, mechanical, and mag­netic) and rest on the technology (nano, surface plasmon resonance (SPR), biosensors-on-chip (lab-on-chip), electrometers, and deployable).
Several types of biosensors have been described here.
2.1.1 Bio-Micro-Electro­Mechanical Systems (Bio­MEMS)
The development of Micro-Electro-Mechanical Systems (MEMS) devices involves a micro-fabrication process utilizing materials such as silicon, glass, and plastic. The process begins with patterning techniques, where photolithography creates desired patterns on the
230 Disha Pant et al.
wafer surface. The wafer is coated with photoresist and exposed to radiation through a mask, transferring the pattern before the pho­toresist is removed [2].
Next, a deposition process applies thin films of various materi­als, such as bioelectronics, polymers like polydimethylsiloxane (PDMS) and polymethylmethacrylate (PMMA), silicon dioxide, silicon nitride, metals for electrodes, or biomolecules, onto the wafer surface. This is followed by etching, which can be either wet (using liquid chemicals) or dry (involving gas-phase chemis­try). Wet etching can be isotropic, etching equally in all directions and causing mask undercutting with a rounded etch profile, or anisotropic, which is directional etching induced by chemical or physical means.
The final step is bonding, where two substrates are joined together through anodic or fusion bonding techniques [
2].
BioMEMS technology has advanced the fabrication of both disposable and implantable drug delivery systems and diagnostic tools. MEMS technology has enabled the creation of microfluidic devices, designed for sensing, pumping, mixing, monitoring, and controlling small fluid volumes. Microneedles, including solid, durable, solid degradable, and hollow types, are used for insulin delivery (e.g., Jewel Pump by Debiotech) and vaccination (e.g., Intaza by Sanofi Pasteur) [
3]. Implantable drug delivery microde-
vices developed with BioMEMS technology aim to address chal­lenges associated with conventional implantable devices, such as unintended drug release (Fig.
2).
Implantable MEMS drug delivery devices contain reservoirs loaded with drugs, which are crucial components. The reservoir materials must be biocompatible externally and inert internally to prevent drug interactions. Common materials include PDMS, polyacrylamide, medical-grade silicone rubber, and Pyrex© due to their desirable properties like biocompatibility, bonding, and opti­cal transparency. Advances in microfabrication have enabled the creation of appropriately sized reservoirs that balance drug load
Fig. 2 Biosensors and drug delivery systems
Biosensor-Based Drug Delivery Systems: Innovations, Applications, and… 231
capacity and effective drug release mechanisms without significantly increasing device size. Miniaturization is essential for initial animal testing and eventual human application, ensuring precise and con­trollable drug delivery.
Micropumps are crucial components in microfluidic drug deliv­ery devices, enabling precise control over drug dosage and release rate in targeted tissues. They can be programmed to administer drugs consistently, preventing fluctuations in drug levels in the bloodstream. Key parameters for micropumps include size, low heat generation, precise metering, low power consumption, and system integration. Micropumps are classified into mechanical (e.g., piezoelectric, magnetic) and non-mechanical (e.g., electro­chemical) types, both of which can be miniaturized for implanta­tion. The need for an external power source and the energy required for operation are critical factors affecting the feasibility of implantation.
Through BioMEMS technology, a piezoelectric pump­controlled drug delivery system has been developed for transdermal insulin delivery via microneedles, improving precision and accuracy compared to mechanically controlled pumps [
4]. To enhance lon-
gevity and biocompatibility, future BioMEMS devices may utilize biodegradable polymers or compounds that mitigate tissue responses, such as antibiotics or anti-inflammatory agents [
5]. Some of the preparations are listed in Table 1.
Table 1 Single reservoir-based MEMS devices for drug delivery applications
Working
S.
Drugs loaded
no.
1. Aqueous solutions
2. Adrenaline Electrochemical PDMS, polyolefin,
3. Methylene blue
Docetaxel
4. Sodium salicylate Phase change Parylene-C
5. Doxorubicin hydrochloride
PDMS, polydimethylsiloxane
mechanism of MEMS
Piezoelectrical Silicon water, silver
Magnetic PDMS,
Electrochemical PDMS
Materials used Dimensions Reference
PDMS
platinum/ titanium
iron oxide particles
PDMS Microtubing Paraffin wax
wafers
Silicon Titanium gold
(8 × 8) mm 100 micron [6]
10 mm × 10 mm × 2mm [7]
5 mm × 3 mm × 12 mm 2 mm × 1 m m× 12 mm
8mm × 8mm × 3mm [9]
mm × 13 mm × 3.5 mm
13
[8]
[10]
232 Disha Pant et al.
While designing the size of the pumping device of MEMS­based delivery systems, its energy consumption, shelf life, and inability to interfere with physiology and feasibility of implantation have to be kept in mind. Among the available options, mechanical pumps like piezoelectric, magnetic and non- mechanical pumps like electrochemical induced forces based pumps are preferred.
Mechanical micropumps conceptualize oscillating diaphragms for moving fluids across pressure gradient. They push and halt fluid and develop a pulsating flow due to their periodicity. Their general construction includes a flexible membrane or diaphragm, an actua­tor, a pumping chamber, an inlet, and an outlet.
Mechanical micropumps, also known as displacement micro­pumps, utilize the movement of components like oscillating dia­phragms to pump fluids by applying pressure. These pumps generate a pulsating flow due to their periodic operation and con­sist of key components such as a flexible membrane or diaphragm, an actuator, a pumping chamber, an inlet, and an outlet. The oscillatory movement of the membrane, driven by a physical actua­tor, creates the pressure difference needed for fluid pumping. Common driving forces in mechanical micropumps for MEMS drug delivery devices include piezoelectric, magnetic, and material phase change mechanisms.
Non-mechanical micropumps
generate
fluid flow by directly exerting forces on the liquid without involving any structural movement. These systems convert a non-mechanical energy source into kinetic energy and typically have a limited flow rate and slower response compared to mechanical micropumps. They often require interaction with a working solution possessing specific electrical properties, such as conductivity. Despite these limitations, non-mechanical micropumps are valuable in drug delivery applica­tions due to their low power consumption. Common actuation methods include electro-hydro-dynamic, magneto-hydrodynamic, electro-osmotic, and electrochemical forces, with electrochemical forces being particularly relevant for drug release applications.
Another g
roup o
f MEMS devices for drug release applications utilizes multiple reservoirs, each designed to deliver a single dose of the loaded drug. These devices employ various actuation mechan­isms to achieve precise and controlled release by promoting the dissolution or rupture of the reservoir capping membranes. Nota­bly, an implantable multi-reservoir device was developed for passive release of chemotherapeutic drugs to test tumor sensitivity in vivo.
This device,
implanted through a biopsy needle, directly deliv­ered drugs into tumor tissue without systemic exposure, using micromachined Delrin acetal resin blocks with 3–30 circular reser­voirs for passive drug release over 24 h. Techniques such as mod­ifying reservoir opening size, using polymer matrices to control drug diffusion, and employing hydrophilic hydrogels to eject
Biosensor-Based Drug Delivery Systems: Innovations, Applications, and… 233
Table 2 Multi reservoir-based MEMS devices for drug delivery applications
Working
S.
Drugs loaded
no.
mechanism of MEMS
Materials used Dimensions Ref erence
1. Human growth hormone NIR irradiation
2. Doxorubicin, sunitinib,
lapatinib, antibody cetuximab, dasatinib, gemcitabine, paclitaxel, cisplatin
3. Human parathyroid
hormone fragment (1–34) [hPTH(1–34)]
4. Mannitol Electrothermal Silicon wafer
Passive release Delrin acetal
Electrothermal Titanium
Graphene
oxide nanoparticles
Polyurethane
medical epoxy Parylene C
resin blocks
housing silicon wafer Ti-Pt
Au or Pt/Ti/Pt membranes
drugs were employed to control the release profile. Additionally, combining drugs in a single reservoir allowed testing of up to 16 drug combinations, enabling optimization of drug therapy before systemic treatment. Table wide using multi reservoir-based MEMS.
27 mm × 11.5 mm
× 9.5 mm
820 μm × 3 mm [12]
13 × 5.4 × 0.5 mm [13]
Not specified [14]
[11]
2 summarizes work done world-
2.1.2 Smart Polymers
Smart polymers are the materials that mimic biological systems, undergoing structural changes in response to external stimuli such as pH, temperature, and ionic variations can also be used as biosensors. These polymers are categorized into three forms based on their physical properties: linear free chains in solutions collapse reversibly upon stimulus application; covalently cross-linked revers­ible gels swell or shrink in response to environmental changes; and chain adsorbed or surface-grafted polymers exhibit reversible swelling or collapse on surfaces when triggers are altered [
They have
the ability to deliver drugs when needed. One such
15, 16].
example is the attachment of both glucose oxidase and insulin within a hydrogel that is responsive to changes in pH, enabling this smart polymer to act both as a sensor of glucose concentration and as a drug delivery vehicle for insulin [
17]. These types of
234 Disha Pant et al.
biosensor-drug delivery systems can reduce the risk of overdosing/ underdosing a patient while allowing the patient to receive the drug at a specific time point.
2.1.3 Microfabricated Devices
Most microfabricated devices function as biosensors, but their utility is often restricted by a short lifespan. Designing implantable biosensors with extended functionality is critical for optimal closed­loop drug delivery or monitoring systems. Addressing challenges such as implant biocompatibility and biofouling is essential for maintaining long-term in vivo sensing.
Enhancing the integration of drug delivery systems with bio­sensor technology can be achieved using hydrogels sensitive to thermal, pH, ionic strength, or biomolecular changes. These mate­rials improve biocompatibility and reduce biofouling.
Innovatively, a cantilever can act as a lid on reservoirs, where a responsive hydrogel containing sensing molecules can control the lid’s opening and closing based on analyte levels. Electrically responsive hydrogels can also be used in MEMS-based sensors or drug delivery devices, enabling external electrical stimulation to trigger drug release.
MEMS technology has been utilized to create microparticles and micro-reservoirs for drug delivery. Microparticles are produced by forming arrays of wells, 25–100 μm in size, within silicon squares measuring 80–150 μm. These wells are filled with drugs and sealed with dissolvable caps that adhere to target sites due to bioadhesive properties, allowing precise drug delivery. Smart polymers capable of shrinking upon analyte detection can enhance these microparti­cles, enabling responsive drug release and integration with biosensors.
For example, micro-reservoirs are made from silicon and capped with gold membranes that rupture upon voltage stimula­tion. Instead of voltage, smart polymers can collapse in response to analyte concentrations or use conductive polymers activated during redox reactions. Overall, microfabricated devices have revolutio­nized the development of controlled-release microchips [
Lab-on-a-chip s
ystems h
ave the edge of rapid and improved
2].
data analysis, and portability of the devices, allowing point of care diagnosis and treatment. Incorporation of a micro-reservoir drug depot, micro-pump, valves, and sensors onto BioMEMS devices allowed responsive and controlled release of drug. This increases bioavailability and reduces incidences of toxicity.
A new
controlled-release microchip has been developed using silicon wafers and various drug reservoirs for both single and mul­tiple drug release [
18]. By incorporating drug-loaded hydrogels,
biosensors, and responsive elements, these devices can interact more seamlessly with biological environments. This integration allows pharmaceutical devices to operate more autonomously within their surroundings, reducing the need for constant human oversight.
Biosensor-Based Drug Delivery Systems: Innovations, Applications, and… 235
Microchips are manufactured using MEMS technology by initi­ally choosing a biocompatible substrate and etching micro­reservoirs to contain therapeutic solutions. The next step involves selecting a conductive sealant, a thin membrane that doubles as an anode. The membrane is specifically chosen to maintain structural integrity in a solution without an applied electrical potential, pre­venting dissolution or rupture.
When considering in vivo implantation, it is crucial to account for the presence of oxygen and chloride ions, which can cause metal corrosion. Microchips offer numerous advantages, such as the abil­ity to pattern multiple micro-reservoirs for holding various drugs. This design prevents mechanical breakdown or drug leakage that may occur due to incomplete lid closure, as there are no moving parts, unlike glucose biosensors. Moreover, microchips eliminate the need for patient or doctor intervention to ensure functionality and can support closed-loop systems when integrated with biosen­sors. Designing disposable chips can further enhance both biosen­sor and drug delivery systems [
2].
2.2 Bioreceptor­Based Biosensors
2.2.1 Enzyme-Based Biosensors
2.2.2 Antibody-Based Biosensors
Based upon the bioreceptors, biosensors are categorized as follows.
These are most common biosensors utilized for detection of fluc­tuating glucose and urea levels in the body. The working principle of an enzyme-based biosensor depends on the catalytic reaction and binding capabilities for the target analyte detection. The concen­tration of enzyme-based biosensors alters depending upon the catalytic transformation of the analyte by the enzyme, inactivation or activation by analyte, and tracking of the alteration of enzyme characteristics. However, the enzyme structure is extremely sensi­tive, which makes it expensive and complicated to improve its sensitivity, stability, and adaptability [
19].
These have an embedded antibody as ligand or they function on the antibody–antigen interaction is called immunosensors. Non-labeled immunosensors are constructed to specifically deter­mine the antigen–antibody complex by estimating the physical changes caused by the development of the complex. In the case of labeled immunosensor, a sensitively detectable label is introduced. Madurro et al. constructed a label-free immunosensor to detect ovarian cancer. The system has a linear relationship of anti-CA125 concentration in the range of 5–80 U mL detection of 1.45 U mL
-1
[19].
-1
, exhibiting a limit of
2.2.3 Aptamer-Based Biosensors
These biosensors utilize aptamers which are synthetic single­stranded nucleic acids (sequences of DNA or RNA) that bind to target molecules selectively and can be folded into two-dimensional (2D) and three-dimensional (3D) structures. In 2D or 3D
236 Disha Pant et al.
structures, the targets have high-binding performance due to greater surface density and less spatial blocking. Due to the nucleic acid character of aptamers, they are structurally and functionally stable over a wide range of temperatures and storage conditions. Unlike antibodies that require biological systems to be generated, aptamers can be chemically synthesized, are stable in a pH range of 2–12, and have certain thermal refolding capabilities. A further benefi
t of aptamers is that they can be chemically modified accord-
ing to the detection
criteria for the target molecule.
By an in vitro selection mechanism, SELEX (Systematic Evolu­tion of Ligands by EXponential enrichment), aptamers can be isolated from oligonucleotides libraries. Several SELEX variants have recently been established, including cell- SELEX, capillary electrophoresis-based SELEX, microfluidics-SELEX, FACS-based SELEX, microtiter plate-SELEX, magnetic bead SELEX, and in vivo SELEX. Optical, electrochemical, and piezoelectric techni­ques are the most frequently used in biosensors [
Depending on
dif
ferent transduction techniques, these biosen-
19].
sors are further categorized as labeled or label-free aptasensors. Surface plasmon resonance (SPR) is the most commonly used method for the label-free optical sensors, whereas fluorescent dyes (fluorescein) are used for label-based optical aptasensors. For track­ing biological systems in real time, fluorescent NPs, such as QDs, provide many benefits over regular fluorescent dyes. To identify targets, such as cancer cells, bacterial spores, and proteins, aptamer­QD conjugates were used. Aptamer capped NIR PbS QDs have been designed to detect thrombin protein, based on selective charge transfer, within 1 min and with a detection limit of ~1 nM. Gold nanoparticles (GNPs) have demonstrated interesting absorp­tion characteristics that vary depending upon their aggregation state. Furthermore, GNPs are more biocompatible, easier to bio­conjugate, and less toxic than QDs [
19].
2.2.4 Whole-Cell-Based Biosensors
These utilize microbes (bacterial, fungi (yeasts and molds), algae, protozoa, and viruses), since they possess potential biorecognition elements, in the construction of whole-cell-based biosensors. They are self-replicating and can produce recognition elements, such as antibodies, without the need for extraction and purification. Com­pared with animal or plant cells, whole-cell-based biosensors are easy to handle and rapidly proliferating. The cells can interact with a wide variety of analytes, display the electrochemical response that a transducer can register, and can transmit (whole-cell-based biosen­sor principle). Owing to their good sensitivity, high selectivity, and capability of detection, these biosensors were successfully employed in environmental monitoring, food analysis, pharmacology, heavy metals, pesticides, detection of organic contaminants, and drug screening. A label-free optical whole-cell Escherichia coli biosensor
Biosensor-Based Drug Delivery Systems: Innovations, Applications, and… 237
2.2.5 Nanoparticle­Based Biosensors
has been developed to detect pyrethroid insecticide exposure with a detection limit of 3 ng mL
0.01–2 ng mL
-1
[19].
-1
in the linear range of
Nanobiosensors operate on a similar principle to their conventional macro- and micro-scale counterparts but are built using nanoscale components for signal or data transformation. They of fer unique advantages over larger counterparts due to their multidisciplinary applications enabled by their nanoscale dimensions.
They are particularly valuable for electrode modification, where they enhance the sensitivity and specificity of electrochemical catal­ysis. Additionally, catalytically active nanomaterials, such as transi­tion metal oxides, have been engineered into nanoenzymes, enabling catalysis of biochemical reactions directly on biosensors.
To enhance NP biosensing performance, they are often coated with various matrices such as metal oxides, silica networks, poly­mers, graphene, fibers, and dendrimers. These coatings serve to improve stability, increase specificity, and enhance sensitivity, tailor­ing the NPs for specific biosensing applications.
Over the past decade, metal oxide-based nanomaterials have found extensive applications across various domains such as elec­trochemistry, magnetism, catalysis, and sensor technology due to their diverse electrical, chemical, and physical properties. Among the commonly utilized metal oxide nanoparticles are copper oxide (CuO), nickel oxide (NiO), iron oxide (Fe (Co oxide (TiO num oxide (MoO
), manganese oxide (MnO2), zinc oxide (ZnO), titanium
3O4
), tin oxide (SnO2), cadmium oxide (CdO), molybde-
2
), and cerium oxide (CeO2). These nanoparticles
3
), cobalt oxide
2O3
exhibit outstanding optical, electronic, magnetic, chemical, mechanical, and catalytic properties.
Gold nanoparticles (NPs), classified among noble metal NPs, are extensively studied and utilized due to their remarkable optical, electronic, and physicochemical properties. They hold significant advantages in biomedical research, including simple synthesis tech­niques, straightforward fabrication procedures, high chemical sta­bility, biocompatibility, wide electrochemical potential range, high catalytic activity, and versatility in nanocomposite forms.
Palladium n
anopart
icles (Pd NPs) offer intriguing potential for biomedical applications due to their high catalytic and sensing activities. Additionally, palladium (Pd) is more abundant than gold (Au) and platinum (Pt), rendering it cost-effective and versa­tile for various sensing applications.
Copper (Cu)
has garnered significant attention as a promising sensing material due to its outstanding electrical conductivity, sta­bility, electrocatalytic properties, and cost-effectiveness compared to noble metals. Recently, Huang et al. investigated electrochemical glucose sensors based on copper nanoparticles (Cu NPs) loaded onto a flexible graphite sheet.
238 Disha Pant et al.
Table 3 Heavy metal-based nano-biosensors
S.
Metal-based
No
nanopartic
1. Titanium dioxide
2. Zinc oxide Carbon monoxide gas 80 ppm [21]
3. Manganese dioxide
4. Nickel oxide Glucose biosensors Detection limit (5.0 × 10
5. Cobalt oxide Glutamate biosensor chip Detection limit of 10 μM. [25]
les Molecule detected Detection limit Reference
Detection of Salmonella
typhimurium
Glucose biosensor Detection limit of 0.05 mmol L
Urea biosensor 1 × 10 Detection of miRNA-141 1 pM to 50 nM and a detection limit of
103 –105 cL mL
high sensitivity of 56.32 μA mmol
-2
1
cm
Detection limit of 0.51 μM with a linear
range
-4
0.2
pM
-1
-10
of 1 μM to 2 0mM
-2
and 8 × 10
M[
-1
and
-
M) [23]
[20]
[22]
[24]
26]
[27]
6. Iron oxide Anticancer drugs tagged to
superparamagnetic
ticles
7 Gold-nickel
bimetallic
nanopar
Non-enzymatic glucose
sensor
Furthermore, metal oxide-based nanoparticles such as ZnO,
, SnO2, and MoO3 have recently gained significant attention
TiO
2
for their versatile applications. ZnO nanoparticles are known for their good electron transfer rate, stability, biocompatibility, and high conductivity. Table 3 shows a list of heavy metal based nano­biosensors
synthesized for detection of biomolecules.

3 Methods

A typical biosensor comprises of five essential components, viz., an analyte, a bioreceptor, a transducer, electronics, and display. An analyte is a molecule whose levels are to be identified. It can be glucose, calcium, or any other biomolecule which acts as a substrate to its respective bioreceptor-like enzymes, antibody, cells, aptamers, nanoparticles, etc., The tranducer then generates signals (optical/ electrical) in proportion to the intensity of analyte bioreceptor interaction (biorecognition). The electrical signals obtained from the transducer are amplified, processed, and quantified by the display unit and made readable at user’s end. Figure 3 expresses the co
mplete picture of the components for a biosensor system.
Glucose (1–1900 μM) and a low
detection
limit (0.063 μM)
[28]
[29]