materials

Review
Biomaterials for Drug Delivery and Human Applications
Paolo Trucillo

Department of Chemical, Materials and Industrial Production Engineering, University of Naples Federico II,
Piazzale V. Tecchio, 80, 80125 Naples, Italy; paolo.trucillo@unina.it; Tel.: +39-32-9656-6043

Abstract: Biomaterials embody a groundbreaking paradigm shift in the field of drug delivery and
human applications. Their versatility and adaptability have not only enriched therapeutic outcomes
but also significantly reduced the burden of adverse effects. This work serves as a comprehensive
overview of biomaterials, with a particular emphasis on their pivotal role in drug delivery, classifying
them in terms of their biobased, biodegradable, and biocompatible nature, and highlighting their
characteristics and advantages. The examination also delves into the extensive array of applications
for biomaterials in drug delivery, encompassing diverse medical fields such as cancer therapy,
cardiovascular diseases, neurological disorders, and vaccination. This work also explores the actual
challenges within this domain, including potential toxicity and the complexity of manufacturing
processes. These challenges emphasize the necessity for thorough research and the continuous
development of regulatory frameworks. The second aim of this review is to navigate through
the compelling terrain of recent advances and prospects in biomaterials, envisioning a healthcare
landscape where they empower precise, targeted, and personalized drug delivery. The potential for
biomaterials to transform healthcare is staggering, as they promise treatments tailored to individual
patient needs, offering hope for improved therapeutic efficacy, fewer side effects, and a brighter
future for medical practice.

Keywords: biomaterials; drug-delivery systems; regenerative medicine; diagnostic tools; targeting

1. Introduction
The advancement of efficient drug-delivery systems is essential for enhancing patient
outcomes across a range of medical conditions [1,2]. Clinical consequences can vary
Citation: Trucillo, P. Biomaterials for significantly based on numerous factors, including the quality of healthcare received
Drug Delivery and Human and the individual patient’s characteristics, thus influencing clinical decision-making [3].
Applications. Materials 2024, 17, 456. Medical conditions are incredibly variable, ranging from acute illnesses like infections and
https://doi.org/10.3390/ma17020456 injuries to chronic diseases such as diabetes. Consequently, patient outcomes can range from
Academic Editor: Romána Zelkó complete recovery to long-term therapies [4,5]. The access to quality healthcare significantly
influences patient outcomes. In developed countries, patients generally benefit from better
Received: 26 December 2023 access to high-quality medical care, resulting in improved outcomes. Conversely, resource-
Revised: 12 January 2024
limited situations, inadequate healthcare infrastructure, a lack of trained personnel, and
Accepted: 16 January 2024
limited access to essential medications and treatments may compromise patient outcomes.
Published: 18 January 2024
Additionally, preventive medicine plays a crucial role in reducing patient side effects,
through proactive measures like routine screenings, vaccinations, lifestyle modifications,
and early disease detection. These measures contribute significantly to improving patient
Copyright: © 2024 by the author.
well-being [6–8]. Furthermore, patient outcomes are not solely determined by medical
Licensee MDPI, Basel, Switzerland. interventions, but also by education, housing, and access to healthy food [9]. Innovative
This article is an open access article materials contribute to advancements in medical technology, offering novel solutions
distributed under the terms and for development and application [10–12]. Breakthroughs in electronics, software, and
conditions of the Creative Commons robotics have been crucial in advancing medical technology. However, the development
Attribution (CC BY) license (https:// and application of innovative materials play a central role in shaping the future of medicine.
creativecommons.org/licenses/by/ This evolution extends beyond previous limits, impacting diagnostic tools, implantable
4.0/). devices, drug-delivery systems, and regenerative medicine. Innovative materials catalyze a

Materials 2024, 17, 456. https://doi.org/10.3390/ma17020456 https://www.mdpi.com/journal/materials

Materials 2024, 17, 456 2 of 27

revolution in medical technology, marked by a multifaceted approach involving materials

science, nanotechnology, and biotechnology. In the context of medical technology, these
materials cover a diverse range, each tailored with specific properties to address unique
healthcare challenges [13–17]. Among these, polymers emerged as vital players, enabling
the creation of biocompatible and bioresorbable structures [18] for medical devices [19,20],
tissue engineering scaffolds [21–23], and drug-delivery systems [20–24].
Biobased and biodegradable polymers offer versatile engineering possibilities, allow-
ing for controlled degradation rates, tailored mechanical properties, and surface charac-
teristics that harmonize with the human body. Innovative polymer materials have led to
the development of bioresorbable stents, transforming cardiology by replacing permanent
metallic stents. These advancements reduce long-term complications and eliminate the
necessity for additional invasive procedures [25–28]. Controlled degradation plays a vital
role in the functionality of medical implants, particularly those with a temporary purpose,
such as stents or scaffolds in tissue engineering. This controlled breakdown aligns with
the healing process, preventing complications associated with permanent implants like
inflammation or the need for additional removal surgeries. Biodegradable materials, in-
cluding polymers like polylactic acid (PLA) or polyglycolic acid (PGA), naturally break
down into non-toxic byproducts, in stark contrast to non-biodegradable materials like
certain metals that can cause long-term complications by remaining in the body indefinitely.
Opting for biodegradable products in medical implants not only reduces the risk of chronic
inflammation but also eliminates the need for additional removal surgeries, aligning with
the objective of enhancing patient outcomes while minimizing overall bodily impact.
Nanomaterials, showcasing remarkable properties at the nanoscale, play a pivotal
role in advancing medical technology [22,29–32]. Their applications span a wide spectrum,
from targeted drug delivery [33–36] to the creation of imaging agents [37–41], and the
development of cutting-edge diagnostic tools [42,43]. Quantum dots, for example, offer
adjustable fluorescence properties, facilitating more precise and efficient imaging, which
is particularly crucial in cancer diagnosis and treatment monitoring [44–46]. Simultane-
ously, the exploration of carbon nanotubes and graphene-based materials is underway,
as they hold potential for developing lightweight and robust medical devices with en-
hanced electrical conductivity, making them ideal for applications like neural interfaces and
prosthetics [47–50]. Biological materials, including biomimetic polymers and biologically
derived substances, are contributing significantly to medical technology by mimicking nat-
ural tissues and structures, thereby enhancing compatibility with the human body [51–54].
Innovations in tissue engineering leverage these biomaterials to construct functional organs
and tissues, potentially alleviating the demand for organ transplantation and reducing
rejection rates. Additionally, bioactive coatings on medical implants, such as artificial joints
and dental implants, promote better integration with surrounding tissues and reduce the
risk of complications [55,56].
Metamaterials are an emerging category of materials [57,58], distinguished by in-
tentionally engineered properties that generally are not possible to find in nature. They
demonstrate promise for medical applications by facilitating the creation of devices en-
dowed with exceptional abilities to manipulate light, sound, and electromagnetic waves.
In medical imaging, metamaterial-based lenses and cloaking devices can lead to improved
diagnostic tools that provide higher resolution and sensitivity [57–61]. These innovations
contribute to early disease detection and personalized treatment planning.
Moreover, innovative materials play a crucial role in the advancement of smart medical
devices. Shape memory alloys, for instance, facilitate the fabrication of self-expanding
stents that can be remotely triggered to change shape, providing precise control during
deployment. This adaptability not only diminishes the invasiveness of surgical procedures
but also enhances patient comfort [25,27,62]. Similarly, conductive polymers and flexible
substrates are essential for the development of wearable medical devices, like biosensors
and electronic skins, which can continuously monitor a patient’s health and transmit
real-time data to healthcare professionals, fostering proactive and personalized care.
Materials 2024, 17, 456 3 of 27

Innovative materials also play a crucial role in advancing regenerative medicine, a

field focused on harnessing the body’s natural healing mechanisms to repair or replace
damaged tissues and organs [63,64]. Scaffold materials with intricate microarchitecture
guide tissue regeneration, while hydrogels provide a supportive environment for stem cell
growth and differentiation. Seeded with cells and bioactive molecules, these biomaterials
hold the potential to revolutionize treatments for conditions ranging from spinal cord
injuries to degenerative diseases.
The utilization of innovative biomaterials, exemplified by bioactive glasses and glass-
ceramics, has opened new avenues in the realm of drug delivery. Many bioactive glasses
and glass-ceramics exhibit exceptional biocompatibility and bioactivity, rendering them
promising candidates for designing advanced drug-delivery systems. These materials
possess the ability to interact harmoniously with the biological environment due to their
controlled degradation rates and surface characteristics. In the context of drug delivery,
these biomaterials offer a versatile platform, enabling the incorporation of therapeutic
agents and facilitating controlled release. The porous structure of bioactive glasses and
glass-ceramics enhances drug-loading capacity while promoting localized and sustained
drug release, leading to improved treatment outcomes. This innovative approach not
only optimizes drug delivery but also harnesses the regenerative properties of bioactive
materials, contributing to the overall efficacy and success of medical interventions.
The main goal of the present work is to highlight the critical importance of biomaterials
in developing effective drug-delivery systems to enhance patient outcomes across a wide
range of medical conditions. Innovative materials are significant in shaping the future
of medicine and playing a role in revolutionizing healthcare. This work also discusses a
multifaceted approach involving materials science, nanotechnology, and biotechnology.
The reference selection criteria are comprehensive, focusing on ensuring relevance and
credibility. References align with the main theme of developing effective drug-delivery
systems and utilizing innovative materials in medical technology. The review emphasizes
biomaterials, polymers, nanomaterials, biomimetic polymers, and metamaterials, exploring
their applications in drug delivery, medical devices, regenerative medicine, and smart
medical devices. Notably, the review provides a contemporary overview by incorporating
recent updates in the field of biomaterials in medical technology. The chosen references
cover a wide range of materials science, nanotechnology, and biotechnology, addressing
applications such as medical imaging, diagnostic tools, tissue engineering, regenerative
medicine, and smart medical devices. The inclusion of references tied to key milestones and
breakthroughs enhances the review’s credibility, ensuring a well-supported exploration of
topics related to medical technology and innovative materials.

2. Biomaterials
Biomaterials, crafted to interact with biological systems, have become a cornerstone in
the realm of drug delivery and various human applications. These materials offer a level of
customization that allows for the precise control of drug-release kinetics, thus significantly
improving bioavailability while enabling the targeting of specific tissues or cells [65]. Bio-
materials, by significantly reducing side effects and improving therapeutic effectiveness,
have expanded their applications beyond medicine, infiltrating diverse scientific and tech-
nological domains [66–68]. Their innate properties and incredible versatility have ushered
in a transformative era in healthcare, research, and innovation, redefining the standards
of patient care and scientific exploration. The crucial importance of biomaterials becomes
particularly apparent in the field of drug-delivery systems. Through careful engineering,
these materials can be finely customized to accommodate a wide range of therapeutic
agents, ensuring the controlled and gradual release of medications over time. This control
capability not only enhances the drug’s efficacy but also minimizes adverse reactions and
side effects, thereby improving patient comfort and compliance [69–72]. Furthermore,
the specificity of biomaterials allows for the targeted delivery of drugs to specific cells or
tissues [73–75]. Beyond their involvement in drug delivery, biomaterials showcase their
Materials 2024, 17, 456 4 of 27

versatility in numerous other medical applications. They act as the fundamental building
blocks for a diverse array of medical devices, encompassing artificial joints, dental implants,
and scaffolds for tissue engineering [76–78]. These materials promote integration with the
body, reducing the risk of complications and enhancing the longevity of such devices.
Biomaterials for drug delivery and human applications constitute a fundamental
support in advancing therapeutic interventions. To meet the diverse and intricate demands
of such applications, several material requirements must be carefully considered. Among
these, particle size is a critical parameter, with nanoparticles being commonly favored
for drug delivery due to their enhanced bioavailability and targeted delivery capabilities.
Additionally, microparticles may find utility in providing sustained drug release. High
surface area, a key consideration, influences the drug-loading capacity and interactions
with biological components, playing a crucial role in controlled release systems. The
biocompatibility of biomaterials is imperative, necessitating materials that are non-toxic
and compatible with biological systems to avoid adverse reactions. Biodegradability is often
preferred, allowing biomaterials to break down over time, reducing the need for surgical
removal. The surface charge and functional groups impact cellular interactions, while
mechanical properties, thermal stability, and sterility ensure the suitability of biomaterials
for various applications. Efficient drug-loading and controlled release mechanisms, along
with adherence to regulatory standards, further contribute to the successful design and
implementation of biomaterials for drug delivery and human applications.
In this field, the carriage mechanisms play a fundamental role in ensuring the effective
and targeted delivery of therapeutic agents. These mechanisms involve the encapsulation,
entrapment, or attachment of drugs within or onto biomaterial carriers. Nanoparticles,
liposomes, microparticles, and hydrogels are among the commonly employed carriers.
Encapsulation involves enclosing drugs within a carrier system, providing protection and
controlled release. Entrapment involves trapping drugs within the carrier matrix, while
attachment refers to the coupling of drugs onto the carrier’s surface. These carriage mech-
anisms serve to enhance drug stability, prolong circulation time, and facilitate specific
localization at the target site, minimizing systemic side effects. Tailoring the carriage
mechanisms allows for precise control over drug-release kinetics, improving therapeutic
efficacy. Furthermore, the design of biomaterial carriers considers factors such as biocom-
patibility, biodegradability, and the ability to respond to environmental stimuli, ensuring a
sophisticated and tailored approach to drug delivery for diverse medical applications.
The influence of biomaterials extends far beyond medical devices, as they play a crucial
role in the field of regenerative medicine. Scaffold materials with intricate microarchitecture
can guide tissue regeneration, offering a promising avenue for constructing functional
organs and tissues [79–82].
The application of biomaterials is constantly extending its impact across diverse
domains, with a notable emphasis in regenerative medicine. Hydrogels, a significant
biomaterial component, exhibit remarkable potential by nurturing the growth and dif-
ferentiation of stem cells, providing promising solutions for conditions like spinal cord
injuries and degenerative diseases. In the ever-evolving landscape of scientific research,
biomaterials showcase versatility, contributing not only to healthcare but also propelling
advancements in biotechnology and nanotechnology.

2.1. Drug-Delivery Systems

One of the most significant applications of biomaterials lies in the design of drug-
delivery systems [83]. These materials can be designed to encapsulate and release phar-
maceutical compounds in a controlled and targeted manner. This approach offers several
advantages, including improved drug efficacy, reduced side effects, and prolonged release
for chronic conditions. For instance, biodegradable polymer nanoparticles can be loaded
with drugs and injected into the body, ensuring a sustained release at the site of action.
Biomaterials for drug-delivery systems can include polymers, lipids, and other materials
Materials 2024, 17, 456 5 of 27

that are used to encapsulate and control the release of drugs. A list of common biomaterials
used in drug-delivery systems is provided below (Table 1).

Table 1. A list of biomaterials used for drug-delivery systems.

Biomaterial Description Applications Ref.

Poly(lactic-co-glycolic acid) Biodegradable copolymer used for sustained
Microspheres, nanoparticles, implants [84]
(PLGA) drug release
Spherical lipid vesicles that can encapsulate
Liposomes Targeted drug delivery, gene therapy [85]
hydrophobic and hydrophilic drugs
Natural polysaccharide derived from algae,
Alginate Controlled drug release, wound healing [86]
forms hydrogels
Chitosan Biopolymer derived from chitin, forms hydrogels Oral drug delivery, wound dressings [87]
Hyaluronic Acid (HA) Natural component of the extracellular matrix Ophthalmic, joint injections, skin creams [88]
Polyethylene Glycol (PEG) Synthetic polymer used to improve drug solubility Nanoparticles, conjugates [89]
Cyclic oligosaccharides used for
Cyclodextrins Increasing drug solubility [90]
drug encapsulation
Highly branched macromolecules with
Dendrimers Targeted drug delivery, gene therapy [91]
precise structures
Polylactic Acid (PLA) Biodegradable polymer Nanoparticles, implants [92]
Self-assembling structures formed by amphiphilic Solubilization and delivery of
Polymeric Micelles [93]
block copolymers hydrophobic drugs
The choice of biomaterial depends on the specific drug and delivery requirements. More detailed information,
such as release kinetics, biocompatibility, and specific drug-delivery applications, would be necessary for a
comprehensive analysis. Additionally, the field of drug delivery is continually evolving, and new biomaterials
and technologies are being developed regularly.

2.2. Tissue Engineering

Researchers developed scaffolds made from biocompatible materials like hydrogels,
ceramics, and polymers to support cell growth and tissue regeneration. These scaffolds
provide a structural framework for cells to attach, proliferate, and differentiate, ultimately
leading to the creation of functional replacement tissues and organs such as bones [94–96].
Tissue engineering involves the use of biomaterials to create functional tissues for regenera-
tive medicine and transplantation. A list of common biomaterials used in tissue engineering
and their applications is proposed in Table 2.

Table 2. A list of biomaterials used for tissue engineering.

Biomaterial Description Applications Ref.

Major structural protein in the Skin, bone, cartilage, nerve, and dental
Collagen [97]
extracellular matrix tissue engineering
Hyaluronic Acid (HA) Natural component of connective tissues Ophthalmic, osteoarthritis, and wound healing [98]
Poly(lactic-co-glycolic acid) Scaffold for various tissues, such as bone, cartilage,
Biodegradable copolymer [99]
(PLGA) and nerves
Skin, cartilage, bone, and vascular
Chitosan Biopolymer derived from chitin [100]
tissue engineering
Decellularized Extracellular
Natural tissue matrix with cells removed Various tissues, including heart, liver, and kidney [101]
Matrix (ECM)
Gelatin Derived from collagen, biocompatible Soft tissue engineering, cell encapsulation [102]
Nerve regeneration, skin, and bone
Silk Natural protein fiber [103]
tissue engineering
Alginate Derived from seaweed, forms hydrogels Encapsulation and 3D printing of cells and tissues [104]
Polycaprolactone (PCL) Biodegradable synthetic polymer Bone and cartilage tissue engineering [105]
Scaffold for various tissues, including bone
Polyglycolic Acid (PGA) Biodegradable synthetic polymer [106]
and cartilage
Polyethylene Glycol (PEG) Biocompatible synthetic polymer Cell encapsulation, vascular tissue engineering [107]
Bioceramics, such as hydroxyapatite and
Calcium Phosphates Bone and dental tissue engineering [108]
tricalcium phosphate
The choice of biomaterial depends on the specific tissue being engineered, the desired properties, and the intended
clinical application. Tissue engineering is a rapidly evolving field, and researchers continually explore new
biomaterials and technologies to enhance tissue regeneration and transplantation.
Materials 2024, 17, 456 6 of 27

2.3. Implantable Devices

The development of implantable medical devices, such as artificial joints, pacemakers,
and stents, heavily relies on biomaterials. These materials must be biocompatible to ensure
they integrate seamlessly with the body’s tissues and do not trigger an immune response.
Biomaterials such as titanium alloys and biodegradable polymers have been instrumental
in enhancing the quality of life for patients in need of such devices. Materials enlisted
in Table 3 should be simultaneously biocompatible, durable, while performing specific
functions. A list of common biomaterials used in implantable devices and their applications
is provided below (Table 3).

Table 3. A list of biomaterials used for implantable devices.

Biomaterial Description Properties/Advantages Ref.

Orthopedic implants (joint replacements,
Titanium and Titanium Alloys Lightweight, strong, corrosion-resistant metals [109]
bone plates)
Stainless Steel Durable, corrosion-resistant steel alloy Stents, orthopedic implants [110]
Cobalt-Chromium Alloys High-strength alloys with excellent wear resistance Orthopedic implants, heart valves [111]
Polyethylene Durable and biocompatible polymer Joint replacements (as bearing surfaces) [112]
Silicone Biocompatible elastomer Breast implants, catheters [113]
Polymethyl
Biocompatible thermoplastic polymer Bone cement for joint replacements [114]
Methacrylate (PMMA)
Polyurethane Flexible and biocompatible polymer Heart valves, catheters, pacemaker leads [115]
Polyetheretherketone (PEEK) Biocompatible thermoplastic polymer Spinal implants, dental devices [116]
Zirconia Bioceramic with excellent mechanical properties Dental implants, hip replacements [117]
Temporary implants and
Poly-Lactic Acid (PLA) Biodegradable polymer [118]
drug-eluting devices
Hydrogels Water-absorbent materials with tunable properties Drug delivery, tissue scaffolds [119]
Nitinol (Nickel-Titanium) Shape memory alloy Stents, guidewires, and orthopedic devices [120]
Tantalum Biocompatible metal with high corrosion resistance Orthopedic implants and bone screws [121]
Also in this case, the choice of biomaterial depends on the specific device, its intended function, and its compati-
bility with the surrounding tissues. Innovations in materials science continue to expand the range of biomaterials
available for implantable medical devices.

2.4. Diagnostic Tools

Biomaterials are also essential in the development of diagnostic tools. Nanoparticles
coated with specific biomolecules can be used to detect diseases at an early stage. For
example, magnetic nanoparticles functionalized with antibodies can bind to cancer cells,
allowing for their magnetic separation and subsequent identification. A list of common
biomaterials employed in the fabrication of diagnostic tools is provided below (Table 4).

Table 4. A list of biomaterials used for diagnostic tools.

Biomaterial Application Properties/Advantages Ref.

Silicon Microfluidic chips, sensors High thermal conductivity, compatibility with electronics [122]
Glass Microscope slides, microfluidics Transparency, chemical resistance, biocompatibility [123]
Polydimethylsiloxane (PDMS) Microfluidic devices Transparency, flexibility, ease of fabrication [124]
Polystyrene (PS) Cell culture dishes, multi-well plates Biocompatibility, rigidity [125]
Polyethylene (PE) Disposable pipettes, tubes Low cost, chemical resistance, ease of molding [126]
Polypropylene (PP) Disposable microplates Chemical resistance, thermal stability [127]
Polycarbonate (PC) Microplates, labware Clarity, durability, heat resistance [128]
Polyurethane (PU) Catheters, tubing Flexibility, durability, biocompatibility [129]
Gold Biosensors, nanoparticles High surface area, conductive properties, bioconjugation [130]
Nitrocellulose Immunoassays, lateral flow assays Rapid capillary flow, protein binding capacity [131]
Hydrogels Drug delivery, biosensors Water absorption, biocompatibility, tunable properties [132]
Paper Lateral flow assays, diagnostic cards Low cost, portability, capillary flow [133]
Biodegradable polymers Controlled drug release Biocompatibility, controlled degradation [134]
Magnetic nanoparticles * Magnetic resonance imaging (MRI) Magnetic properties for contrast enhancement [135]
* In medical imaging, particularly techniques like magnetic resonance imaging (MRI), contrast agents are often
employed to enhance the visibility of specific tissues or structures. These contrast agents, which possess magnetic
properties, are introduced into the body to create a clearer distinction between different tissues, leading to
improved imaging results.
Materials 2024, 17, 456 7 of 27

Table 4 provides a general overview of some biomaterials commonly used in diagnostic

tools, and there are many other specialized materials and combinations used for specific
applications within the field of diagnostics.

2.5. Regenerative Medicine

Researchers have unlocked the intriguing potential of biomaterials within the field
of regenerative medicine. Notably, stem cell therapy frequently utilizes scaffolds and
matrices crafted from biomaterials to direct the transformation of stem cells into specific
cell types. This presents a hopeful prospect for addressing ailments such as spinal cord
injuries, neurodegenerative diseases, and heart damage. In Table 5, a list of commonly
utilized biomaterials in regenerative medicine is reported.

Table 5. A list of biomaterials used for regenerative medicine.

Biomaterial Application Properties/Advantages Refs.

Collagen Tissue engineering, wound healing Natural component of extracellular matrix, biocompatible [136]
Hyaluronic Acid Dermal fillers, tissue scaffolds High water-binding capacity, lubrication, biocompatible [137]
Chitosan Scaffolds, drug delivery Biodegradable, biocompatible, antimicrobial properties [138]
Alginate Cell encapsulation, tissue engineering Gel-forming, biocompatible, ease of shaping [139]
Poly(lactic-co-glycolic acid) Drug delivery, scaffolds Biodegradable, tunable degradation rates, biocompatible [140]
Retains natural extracellular matrix, minimizes
Decellularized Tissues Organ and tissue transplantation [141]
immune response
Hydroxyapatite Bone grafts, dental applications Similar composition to bone mineral, osteoconductive [138]
Demineralized Bone Matrix (DBM) Bone regeneration Osteoinductive properties, supports new bone growth [142]
Polycaprolactone Scaffolds, tissue engineering Biodegradable, mechanical strength [143]
Fibrin Wound healing, tissue engineering Natural clotting protein, supports cell migration [144]
Silk Fibroin Tissue scaffolds, drug delivery Biocompatible, mechanical strength, tunable degradation [145]
PEG Hydrogels, drug delivery Biocompatible, tunable properties [146]
Stem Cells Regeneration of various tissues Pluripotent or multipotent cells for tissue repair [147]
ECM Tissue engineering, wound healing Retains tissue-specific structural cues, promotes cell adhesion [148]
Regenerative medicine involves a wide range of biomaterials tailored for specific applications, and this table
provides a general overview of some commonly used materials in the field.

2.6. Drug Screening and Research

Several innovative biomaterials are being employed to generate three-dimensional cell
cultures, commonly referred to as organoids or spheroids. These systems mimic the in vivo
environment more closely than traditional two-dimensional cell cultures, allowing for more
accurate drug screening and testing. Table 6 contains a list of specific biomaterials commonly
used in drug screening and research, along with their applications and advantages.

Table 6. A list of biomaterials used for drug screening and research.

Biomaterial Application Properties/Advantages Refs.

HEK 293 Cells Protein expression, drug target validation. High transfection efficiency, widely used. [149]
MCF-7 Cells Breast cancer research, drug screening. Representative for breast cancer. [150]
A549 Cells Lung cancer and respiratory disease drug studies. Relevant for lung cancer. [151]
HUVEC (Human Umbilical Vein Endothelial Cells) Vascular and cardiovascular drug research. Mimic human vascular conditions. [152]
CaCO-2 Cells Drug transport and oral absorption studies. Representative of the intestinal barrier. [153]
iPSCs (Induced Pluripotent Stem Cells) Disease modeling and personalized medicine. Generated from patient cells. [154]
3D Cell Models Physiologically relevant cell behavior studies. Recapitulate tissue-like environments. [155]
Hepatocytes Liver metabolism and toxicity studies. Essential for liver drug metabolism research. [156]
THP-1 Cells Inflammation and immune response drug research. Immunology and drug screening. [157]
Tumor Xenograft Models Replicate human cancer for in vivo drug testing. Mimic human cancer conditions for testing. [158]
High-throughput screening and developmental
Zebrafish Models Transparent embryos for live imaging. [159]
studies.
Human Tissue Microarrays Tissue sample analysis and biomarker identification. Efficient analysis of multiple samples. [160]
Chitosan-Based Hydrogels Tissue engineering and controlled drug delivery. Biocompatible, versatile scaffold. [161]
PLGA Nanoparticles Drug encapsulation and targeted drug delivery. Controlled release. [162]
Monoclonal Antibodies Biologic drug development and immunotherapy. High specificity and therapeutic potential. [163]
Peptide Nucleic Acids Genetic research, molecular biology, and gene therapy. Sequence-specific hybridization. [164]
These specific biomaterials offer distinct advantages in drug screening and research, enhancing the ability of
researchers to conduct experiments, develop drugs, and understand disease mechanisms more effectively.

2.7. Bioimaging
Biomaterials are also used as contrast agents in various imaging techniques, such as
magnetic resonance imaging (MRI) and ultrasound. These materials enhance the visibility
Materials 2024, 17, 456 8 of 27

of specific tissues or structures, aiding in the diagnosis and monitoring of diseases. Table 7
reports a list of specific biomaterials commonly used in bioimaging, along with their
applications and advantages.

Table 7. A list of biomaterials used for bioimaging.

Biomaterial Application Properties/Advantages References

High brightness, tunable emission,
Quantum Dots Fluorescent labeling for cellular and molecular imaging. [165]
and photostability.
Fluorescent Proteins Tagging proteins and tracking cellular processes. Genetically encoded, non-invasive imaging. [166]
Gold Nanoparticles Contrast agents for electron microscopy and optical imaging. Excellent light scattering and high contrast. [165]
Iron Oxide Nanoparticles Magnetic resonance imaging (MRI) contrast agents. High relaxivity for sensitive MRI detection. [167]
Upconversion Nanoparticles Multispectral imaging and deep tissue imaging. Low autofluorescence and minimal photodamage. [168]
Carbon Nanotubes Optical imaging and drug-delivery carriers. Strong absorbance in the near-infrared region. [169]
Fluorescent Dyes Versatile for various bioimaging techniques. Bright fluorescence and broad color range. [170]
Liposomes Drug delivery and encapsulation of imaging agents. Easy modification and controlled drug release. [171]
Magnetic Nanoparticles Magnetic resonance imaging (MRI) contrast agents. Safe and non-toxic for in vivo imaging. [172]
Silica Nanoparticles Labeling and tracking cellular events. High stability and easy surface functionalization. [173]
Gold Nanorods Imaging and photothermal therapy applications. Strong absorbance in the near-infrared region. [174]
Biosensors Detect and quantify specific biomolecules in real-time. High sensitivity and specificity. [175]
Nanodiamonds Multimodal imaging, including MRI and fluorescent imaging. Stable and long-lasting fluorescence. [176]
Optical Coherence
Enhance depth-resolved imaging in ophthalmology. Real-time imaging and non-invasive. [177]
Tomography (OCT)
Peptide Nanotubes Cellular imaging and drug delivery. Biocompatibility and ease of functionalization. [178]
These specific biomaterials offer distinct advantages in bioimaging, allowing researchers and clinicians to visualize
and understand biological processes, diseases, and structures with precision and efficiency.

2.8. Vaccine Development

Biomaterials are playing a crucial role in vaccine development, particularly in the
context of mRNA vaccines like those developed for COVID-19. Lipid nanoparticles serve
as carriers for the fragile mRNA molecules, protecting them and facilitating their delivery
into cells to trigger an immune response. A list of specific biomaterials commonly used in
vaccine development is provided below (Table 8).

Table 8. A list of biomaterials used for vaccine development.

Biomaterial Application Properties/Advantages References

Adjuvants (Aluminum salts) Enhance immune response and vaccine efficacy. Proven safety and effectiveness in many vaccines. [179]
Virus-like Particles (VLPs) Mimic viral structures to stimulate the immune system. Safer than using live or inactivated viruses. [180]
Recombinant Proteins Present antigens to induce specific immune responses. Highly purified and well-defined antigens. [181]
Deliver genetic material encoding antigens for
DNA Vaccines Easy production and modification. [182]
immune response.
Use synthetic mRNA to instruct cells to Rapid development and potential for
mRNA Vaccines [183]
produce antigens. personalized vaccines.
Modified viruses deliver antigens to trigger
Viral Vector Vaccines Strong and long-lasting immune responses. [184]
immune response.
Use weakened forms of pathogens for
Live Attenuated Vaccines Often provide robust and long-lasting immunity. [185]
immune stimulation.
Inactivated Vaccines Use killed pathogens to induce an immune response. Safer than live vaccines but still provide protection. [186]
Deliver antigens and adjuvants to enhance
Nanoparticles (e.g., liposomes) Improved stability and immune response. [187]
vaccine performance.
Protein Subunit Vaccines Use purified pieces of pathogens as antigens. Safe and well-tolerated, no risk of causing disease. [188]
Combine virus vectors with subunit antigens for strong
Virus Vectored Subunit Vaccines Induce both cellular and humoral immune responses. [189]
immune response.
Polysaccharide Conjugate Link bacterial polysaccharides to proteins for better
Effective against bacterial diseases. [190]
Vaccines immune recognition.
Deliver mRNA and other vaccine
Lipid Nanoparticles (LNPs) Facilitate cellular uptake and mRNA translation. [191]
components efficiently.
Use cultured cells to produce antigens for
Cell-Based Vaccines Scalable and adaptable for various pathogens. [192]
vaccine development.
Utilize adenoviruses to deliver genetic material for Strong immune responses, particularly against
Adenovirus-based Vaccines [193]
antigen production. viral diseases.
These biomaterials offer distinct advantages in vaccine development, while preventing a wide range of infec-
tious diseases.

3. Synthetic, Biobased, and Biodegradable Biomaterials

Derived from renewable biological sources like plants, animals, or microorganisms,
biobased materials are environmentally friendly substances. Among these, biodegradable
materials have a unique ability to naturally decompose or transform into simpler com-
pounds over a short period, facilitated by microorganisms like bacteria and fungi. This
Materials 2024, 17, 456 9 of 27

subset of biomaterials plays a crucial role in medical science and material engineering,
where categorization based on degradability is fundamental. Biomaterials are broadly
classified into two categories: biodegradable and non-biodegradable. Biodegradable ma-
terials, including magnesium-based alloys and natural biopolymers like chitosan and
collagen, break down over time, allowing natural absorption or excretion by the body.
For instance, magnesium-based alloys are renowned for their orthopedic implants and
underscore the importance of biodegradability in minimizing long-term impact. In contrast,
non-biodegradable materials, such as certain metals and synthetic polymers, maintain
structural integrity for extended periods, crucial for applications demanding long-term
stability in medical devices. Additionally, biobased materials, or biomass-based materials,
are derived from renewable biological sources and can be further categorized based on their
biodegradability and compatibility with biological systems. These materials, which include
biodegradable substances capable of breaking down into non-toxic compounds, water,
and carbon dioxide, are intended for safe use within the human body or other biological
environments, minimizing adverse effects [194]. These materials are intended to be safe
for use within the human body or other biological environments without causing toxicity,
inflammation, rejection, or other negative effects.
Among biodegradable polymers [195], polybutylene succinate (PBS) is a biobased poly-
mer derived from succinic acid and 1,4-butanediol, which can be obtained from renewable
sources like corn. It is biodegradable and used in packaging and agricultural films; more-
over, polyglycolic acid (PGA) is a biobased and biodegradable polymer used in medical
sutures and other biomedical applications; Poly-3-hydroxybutyrate-co-3-hydroxyvalerate
(PHBV) is a biodegradable copolymer produced by certain bacteria and can be used in
various applications, including packaging and medical devices; starch blends, with other
biodegradable polymers, can result in materials that are both biobased and biodegradable.
These blends are used in items like biodegradable bags and packaging; certain forms
of polyethylene glycol (PEG) are biodegradable. They are used in various medical and
pharmaceutical applications.
Concerning biobased and non-biodegradable polymers [196], polylactic acid (PLA) is
obtained from fermented plant starch, usually corn. While it is often considered biodegrad-
able under industrial composting conditions, it may not readily biodegrade in natural
environments; moreover, polyethylene (PE) is a biobased and non-biodegradable polymer
made from sugarcane: some companies produce a type of polyethylene using biobased
ethylene derived from sugarcane ethanol. While this reduces the carbon footprint, it does
not necessarily make the polymer biodegradable; polyethylene terephthalate (PET) is a
biobased and non-biodegradable polymer made from plant sources: plant-based PET
is derived from biobased ethylene glycol made from renewable sources like sugarcane.
However, the resulting PET is not biodegradable; polyamides (Nylon) is a biobased and
non-biodegradable polymer made from castor oil: some biobased polyamides are pro-
duced using castor oil, which is a renewable resource. These materials can have improved
sustainability but are generally not biodegradable.
A non-biobased and biodegradable polymer [197] is polybutylene adipate terephtha-
late (PBAT), which is commonly used in compostable plastic products; polycaprolactone
(PCL) is a non-biobased, biodegradable polymer used in various applications, including
drug-delivery systems and 3D printing; polyvinyl alcohol (PVA) is a synthetic polymer that
can be made biodegradable and is used in applications like water-soluble packaging films;
polyethylene oxide (PEO) is a synthetic polymer that is water-soluble and biodegradable
under certain conditions.
The last member of this classification is polyethylene (PE), a non-biodegradable poly-
mer [198,199]. It is used in various applications, including plastic bags and containers;
polypropylene (PP) is another common non-biodegradable polymer used in products such
as packaging, automotive parts, and textiles; polyvinyl chloride (PVC) is a versatile syn-
thetic polymer but is not biodegradable. It is used in construction materials, pipes, and
vinyl products; polystyrene (PS) is non-biodegradable and is used in disposable cutlery,
Materials 2024, 17, 456 10 of 27

packaging materials, and foam products; polyethylene terephthalate (PET) is widely used
for plastic bottles and containers but is not biodegradable; polyurethane (PU) is a non-
biodegradable polymer used in a wide range of applications, including foam insulation
and flexible foam products; acrylonitrile butadiene styrene (ABS) is a non-biodegradable
polymer commonly used in 3D printing and automotive components; polycarbonate
(PC) is used in eyeglass lenses, CDs/DVDs, and various industrial applications and is
not biodegradable.
A diverse range of biomaterials have a fundamental role in medicine and biomedi-
cal engineering, each selected for specific applications based on their unique properties.
Polymeric biomaterials, like PE, PU, PLGA, and PEG, are widely used in medical devices
and drug delivery. Metals such as titanium and stainless steel are preferred for orthopedic
and dental implants, while ceramics like hydroxyapatite find use in similar scenarios.
Natural polymers such as collagen and chitosan are integral to tissue engineering, and
biodegradable polymers like PLA, PGA, and PCL are essential in drug delivery and tissue
engineering. Hydrogels, including polyacrylamide and polyethylene glycol diacrylate
(PEGDA), play pivotal roles in both drug delivery and tissue engineering. Composite
biomaterials, like carbon fiber-reinforced polymers, offer versatile solutions to complex
biomedical challenges.
Cutting-edge biomaterials revolutionize diverse medical applications, providing solu-
tions for bioresorbable needs through engineered alternatives like bioresorbable magnesium
alloys. Biomimetic materials, inspired by natural tissues, play a crucial role in tissue engi-
neering, with examples including silk-based biomaterials and extracellular matrix (ECM)
analogs. Nanomaterials, such as gold nanoparticles, carbon nanotubes, and nanofiber
scaffolds, offer precision in drug delivery, imaging, and tissue engineering at the nanoscale.
Some biomaterials sourced from biology involve decellularized tissues, xenografts (e.g.,
pig heart valves), and autografts (e.g., a patient’s tissue). Synthetic biodegradable poly-
mers like PLA, PGA, and PCL ensure controlled degradation, vital for gradual medical
applications. This diverse array of biomaterials showcases the forefront of medical science,
delivering innovative solutions for a wide range of healthcare challenges. In drug delivery,
biomaterials take various forms—polymers, lipids, nanoparticles, hydrogels—each selected
for unique advantages in line with therapeutic goals and drug properties.

3.1. Synthetic and Natural Polymers

Synthetic and natural polymers, such as polyethylene glycol (PEG), polylactic acid
(PLA), and chitosan, play a crucial role in drug delivery by providing a versatile platform
for controlled release and encapsulation. PEG’s hydrophilicity and biocompatibility allow
precise customization for diverse therapeutic agents, ensuring distinct release kinetics. PLA,
a biodegradable synthetic polymer, enables sustained drug release with controlled degra-
dation rates, reducing administration frequency and minimizing side effects. Chitosan, a
natural polymer derived from chitin, offers a biodegradable alternative with mucoadhesive
properties, facilitating controlled drug release and absorption across biological barriers.
The tunable properties of these polymers are paramount in optimizing drug-release profiles,
delivering therapeutic agents effectively while minimizing side effects. This capability is
essential for various applications, from managing chronic pain with gradual painkiller re-
lease to targeted anticancer drug delivery. Additionally, these polymers address challenges
related to patient compliance by reducing dosing frequency and enhancing adherence,
particularly in chronic conditions where frequent dosing may be burdensome. Therefore,
both synthetic and natural polymers have redefined the landscape of drug delivery by
offering tunable properties that enable precise control over drug encapsulation and release.
PEG, PLA, and chitosan exemplify this adaptability, each with unique characteristics that
cater to a wide range of therapeutic needs. The ability to customize drug-release profiles
has revolutionized patient care by improving treatment efficacy, reducing side effects, and
enhancing patient compliance. As pharmaceutical science continues to evolve, polymers
Materials 2024, 17, 456 11 of 27

will undoubtedly remain at the forefront of innovation, providing versatile solutions to

complex drug delivery challenges and advancing the field of medicine.

3.2. Lipid-Based Nanocarriers

The role of lipids in drug delivery has evolved significantly, with lipid-based nanocar-
riers like liposomes and lipid nanoparticles becoming integral tools in the pharmaceutical
industry [200]. These carriers are specifically designed to encapsulate hydrophobic drugs,
offering solutions to the persistent challenge of enhancing the solubility and stability of
advanced therapeutic agents.
Liposomes, which consist of a lipid bilayer surrounding an aqueous core, have gained
prominence as versatile drug-delivery vehicles [201]. The lipid bilayer mimics the structure
of biological membranes, making liposomes inherently biocompatible. This biocompatibil-
ity reduces the likelihood of adverse reactions, making liposomes a safe choice for drug
encapsulation. Moreover, the lipid composition can be tailored to achieve the desired
drug-release profile, further highlighting their versatility. By incorporating hydrophobic
drugs into the lipid bilayer, liposomes can increase the solubility of these compounds in
aqueous environments. This is a crucial advantage, as many drugs with potent therapeutic
properties are inherently hydrophobic, posing challenges for their formulation and ad-
ministration. Liposomes not only enhance drug solubility but also protect the drug from
degradation, extending its shelf life and ensuring that the therapeutic payload remains
intact until it reaches its intended target within the body.
Lipid nanoparticles represent another powerful lipid-based nanocarrier option. They
are typically composed of lipids and are smaller in size compared to liposomes, enhancing
drug-loading capacity in some specific circumstances, for example when dealing with
highly potent yet hydrophobic drugs [202]. Notably stable, lipid nanoparticles are suitable
for prolonged storage and distribution. A key advantage lies in their ability to enable con-
trolled drug release for hydrophobic drugs, achieved by manipulating lipid composition
to fine-tune release kinetics. This feature is crucial for maintaining specific drug concen-
trations in the bloodstream for successful treatment. The modification of lipid surface
properties further allows for targeted drug delivery, enhancing precision and efficiency
while minimizing off-target effects through functionalization with ligands or antibodies.
The transformative impact of lipid-based nanocarriers spans various medical fields. In
oncology, liposomes and lipid nanoparticles enhance chemotherapeutic agent delivery,
increasing solubility, reducing systemic toxicity, and improving selectivity for cancer cells.
These carriers play a pivotal role in effectively delivering hydrophobic antimicrobial agents
in infectious disease treatment. Additionally, they find application in encapsulating and
delivering genes and nucleic acid-based therapies, addressing unique challenges associated
with these emerging treatments [203–205].
Lipid-based nanocarriers, such as liposomes and lipid nanoparticles, represent a
remarkable achievement in the field of drug delivery. They have revolutionized the ad-
ministration of hydrophobic drugs, improving their solubility, stability, and therapeutic
efficacy. The versatility, biocompatibility, and tunable properties of these carriers make
them invaluable tools for the pharmaceutical industry. As research in drug delivery contin-
ues to advance, lipid-based nanocarriers will undoubtedly remain at the forefront, offering
innovative solutions to improve the treatment of various diseases and enhance the overall
patient experience [206].

3.3. Nanoparticles
Polymeric nanoparticles can be fabricated starting from biocompatible polymers and
have emerged as a cornerstone of modern drug delivery. Their versatility and adaptability
make them ideal candidates for encapsulating therapeutic agents, enabling precise drug
delivery to specific tissues or cells [207]. One of the most remarkable features of polymeric
nanoparticles is their ability to accommodate a diverse range of drugs, from hydrophobic
compounds to hydrophilic molecules. By selecting the appropriate polymer and formula-
Materials 2024, 17, 456 12 of 27

tion, researchers can tailor the nanoparticles to accommodate the specific physicochemical
properties of the drug. This versatility is crucial in addressing the individualized needs of
various pharmaceutical compounds and therapeutic scenarios.
Moreover, polymeric nanoparticles offer controlled drug release, allowing for the
gradual and sustained release of the encapsulated drug [208]. This controlled release mech-
anism is essential for maintaining therapeutic concentrations of the drug over an extended
period, thereby enhancing its efficacy while reducing potential side effects. The ability to
fine-tune the release profile through polymer selection and nanoparticle design has opened
new horizons for personalized medicine, ensuring that treatment regimens are tailored to
the unique requirements of patients. Beyond drug delivery, polymeric nanoparticles serve
as valuable tools in medical imaging. By loading these nanoparticles with imaging agents,
they become potent contrast agents in various imaging modalities such as magnetic reso-
nance imaging (MRI) and fluorescence imaging. The incorporation of fluorescent dyes or
other contrast agents into the nanoparticles enhances the precision and sensitivity of these
imaging techniques. This is particularly significant in disease diagnosis and monitoring, as
it allows healthcare professionals to visualize specific biological structures or pathological
conditions with unprecedented clarity, often in their earliest stages.
Inorganic nanoparticles, such as gold and silver nanoparticles, bring remarkable capa-
bilities to medical applications. Gold nanoparticles, known for surface plasmon resonance,
enhance medical imaging through exceptional light absorption and scattering tunability.
Used as contrast agents in computed tomography (CT) scans, they provide high-resolution
imaging, crucial for detailed anatomical and pathological insights. Gold nanoparticles
also excel in targeted drug delivery by functionalizing surfaces with ligands or antibodies,
ensuring precise delivery and maximizing therapeutic efficacy while minimizing dam-
age to healthy tissue. This dual role has propelled theranostics, promising personalized
medicine at the intersection of therapy and diagnostics. Silver nanoparticles, with in-
trinsic antimicrobial properties, find applications in wound care, creams, and dressings,
controlling infections through controlled silver ion release. Their adaptability in serving
as both targeted drug-delivery vehicles and infection control agents showcases their ver-
satility in medicine. Nanoparticles, whether polymeric for customizable drug delivery
or inorganic like gold and silver for advanced imaging and therapy, mark a new era in
precision medicine. Their biocompatibility, tunability, and versatility offer solutions to
diverse medical challenges, paving the way for more effective treatments, early disease
detection, and personalized patient care.

3.4. Hydrogels
Hydrogels are a remarkable class of materials that have carved a niche for themselves
in the fields of drug delivery and tissue engineering. These three-dimensional networks
of hydrophilic polymers, typically water-swollen, provide an ideal environment for drug
release and serve as versatile scaffolds in the burgeoning world of regenerative medicine.
Hydrogels’ unique characteristics, including biocompatibility, tunable properties, and con-
trolled drug-release capabilities, have positioned them as a central player in revolutionizing
how we administer drugs and repair or regenerate damaged tissues. Biocompatibility
is a cornerstone of hydrogels, making them particularly well-suited for a wide array of
biomedical applications. Their high-water content closely mimics the aqueous environment
of living organisms, minimizing adverse reactions and inflammation when introduced into
the body. This biocompatibility ensures that hydrogels can be used safely for prolonged
periods, crucial for applications in tissue engineering and sustained drug delivery [86,87].
Hydrogels, with their tunable properties, play a pivotal role in revolutionizing drug
delivery and tissue engineering. The ability to precisely adjust their chemical composition
and physical characteristics makes hydrogels adaptable to diverse applications. In drug
delivery, hydrogels serve as a sophisticated platform for controlled drug release, enabling
the customization of release profiles for different therapeutic agents. This controlled release
is vital for managing chronic conditions, enhancing patient adherence, and minimizing
Materials 2024, 17, 456 13 of 27

side effects. Hydrogel-based drug-delivery systems can be engineered for single doses
or sustained release over extended periods. Their biocompatibility and controlled release
properties find applications in targeted drug delivery, such as releasing anticancer agents
directly into tumor tissues, reducing systemic exposure, and improving treatment efficacy
with fewer side effects. In tissue engineering, hydrogels act as indispensable scaffolds for
tissue regeneration, mimicking the natural extracellular environment and facilitating the
development of functional replacement tissues. Researchers have leveraged hydrogels
to engineer various tissues, from cartilage and bone to skin, and even organs like the
liver and heart. This has transformative implications for organ transplants, offering the
promise of personalized, lab-grown organs and tissues to address the shortage of donor
organs and reduce the risks of rejection. Hydrogels, with their biocompatibility, tunable
properties, and controlled drug-release capabilities, represent a significant leap forward
in biomedical applications. They continue to shape the future of healthcare by providing
novel solutions to complex medical problems, promising more effective and personalized
medical treatments through ongoing research and innovation [94–96].

4. Design Principles for Biomaterial-Based Drug-Delivery Systems

The design of biomaterial-based drug-delivery systems requires a multidisciplinary
approach, considering several key principles [27,131,189,194,209–218].

4.1. Biocompatibility
Biomaterials play a vital role in medicine, serving as medical devices, drug-delivery
carriers, tissue scaffolds, or imaging agents. Biocompatibility is a fundamental requirement
for biomaterials, ensuring their ability to interact with biological systems without causing
adverse reactions of toxicity. Biocompatibility is crucial as incompatible materials can
trigger immune responses, inflammation, and complications [219]. Avoiding immune
reactions is essential to prevent complications, implant failure, or rejection. Rigorous
testing, including in vitro and in vivo assessments, is necessary to ensure biomaterials’
biocompatibility and safety for medical applications. Understanding these interactions is
pivotal for designing biomaterials that effectively coexist with biological environments.
Biomaterials must be designed with molecules and structures that the body can recog-
nize or metabolize, reducing the risk of adverse reactions [220]. Synthetic polymers, metals,
ceramics, and natural polymers each have unique chemical properties that can affect their
biocompatibility. Surface properties are equally significant. The surface of a biomaterial
can directly influence how it interacts with the biological environment. Surface modifi-
cation techniques, such as coatings or functionalization, are often employed to enhance
biocompatibility by promoting cell adhesion and reducing immune recognition. Moreover,
the physical properties of biomaterials, such as their mechanical strength, flexibility, and
degradation rate, can also impact biocompatibility. These properties must align with the
specific application of the biomaterial. For instance, orthopedic implants need to possess
adequate mechanical strength to support the body’s weight, while biodegradable polymers
used in tissue engineering should degrade at a controlled rate without causing harm.
In recent years, advancements in biomaterial science have led to the development of
smart biomaterials that respond dynamically to the surrounding biological environment,
further enhancing biocompatibility. These materials can release drugs, grow with tissues,
or adapt their properties to accommodate changes in the body, reducing the likelihood of
adverse reactions and improving patient outcomes. In conclusion, biocompatibility is a
fundamental and non-negotiable aspect of biomaterial design and development. Ensuring
that biomaterials do not induce adverse reactions when interacting with biological systems
is essential for the success of medical procedures, devices, and therapies. Biocompatibility
testing and the careful consideration of chemical, surface, and physical properties are
integral to creating biomaterials that seamlessly integrate with the human body, ultimately
advancing the field of medicine and improving the quality of patient care.
Materials 2024, 17, 456 14 of 27

4.2. Drug-Loading and Release Kinetics

Control over drug-loading and release rates is essential to optimize therapeutic efficacy.
In the field of biomaterials, one of the main objectives is to harness precise control over the
loading and release of therapeutic agents [221]. This meticulous control is imperative to op-
timize the therapeutic efficacy of drug-delivery systems. The ability to govern drug-loading
and release rates is a fundamental concept that underpins the design and development
of biomaterials, enabling tailored, patient-specific treatment regimens and minimizing
the potential for adverse effects. Synthetic polymers, natural polymers, liposomes, and
nanoparticles are among the commonly employed biomaterials, each offering unique ad-
vantages for drug loading. The loading capacity of a biomaterial is dictated by its physical
and chemical properties, such as pore size, surface area, and affinity for the drug of interest.
Precise control over these characteristics allows researchers to fine-tune the amount of the
drug that can be accommodated. This is particularly significant when dealing with drugs
with varying potencies or therapeutic ranges, as it enables the customization of drug load-
ing to match the specific needs of the patient or medical condition. Tailored drug loading is
not only vital for efficacy but also helps to minimize the potential for overmedication or
underdosing, thereby reducing the risk of adverse reactions or treatment failure.
Control over drug-release rates is the complementary facet of this concept, ensur-
ing that the drug is administered in a manner that maximizes its therapeutic benefits.
The rate at which a drug is released from the biomaterial carrier directly influences its
pharmacokinetics—how it is absorbed, distributed, metabolized, and excreted within the
body. The controlled release of a drug ensures that it maintains a therapeutic concentration
within the bloodstream, allowing for consistent and sustained therapeutic effects. For drugs
that require prolonged action or need to be administered at specific intervals, controlling
the release rate is critical. Biomaterials can be engineered to facilitate drug release over
varying timescales, from immediate release to extended release over days, weeks, or even
months. By manipulating factors such as the biomaterial’s composition, porosity, and
degradation rate, researchers can fine-tune the drug-release kinetics to meet the unique
requirements of the drug and the patient’s medical condition.
In situations where the therapeutic agent has a narrow therapeutic index or exhibits
dose-dependent effects, controlling the release rate becomes even more crucial. For example,
in the treatment of certain chronic conditions like diabetes or chronic pain management,
maintaining a steady, controlled release of medication is essential to avoid peaks and
troughs in drug concentration that can lead to unwanted side effects or inadequate symptom
control. This concept of controlling drug-loading and release rates finds applications in a
wide array of clinical scenarios. In cancer therapy, for instance, drug-loaded nanoparticles
with tunable release rates can be used to precisely deliver chemotherapeutic agents to tumor
sites, minimizing collateral damage to healthy tissues and maximizing the therapeutic effect
on cancer cells. In the realm of pain management, opioid medications can be delivered
using controlled release formulations, reducing the risk of addiction and overdose.
The ability to customize drug-delivery profiles for individual patients is at the forefront
of innovation. It allows healthcare providers to optimize treatment regimens based on a
patient’s unique physiological characteristics and medical history, ultimately improving
the efficacy and safety of drug therapy. Concerning biomaterials, control over drug-loading
and release rates is an indispensable concept that forms the cornerstone of drug-delivery
systems. It enables the precise customization of drug administration to match the specific
needs of patients and medical conditions. This tailored approach not only enhances
therapeutic efficacy but also minimizes the potential for adverse reactions, advancing
the field of medicine and improving patient outcomes. The capability to harness this
control is instrumental in the development of innovative drug-delivery technologies and
personalized treatment strategies that hold great promise for the future of healthcare.
Materials 2024, 17, 456 15 of 27

4.3. Targeting and Specificity

Biomaterials can be engineered to target specific cells, tissues, or organs, reducing
off-target effects. Biomaterials have ushered in a new era of precision in medicine, offering
the remarkable capability to be engineered with specificity, enabling them to target specific
cells, tissues, or organs within the human body. This concept of targeted drug delivery
through biomaterials has far-reaching implications, as it not only enhances the therapeutic
efficacy of treatments but also minimizes off-target effects, ushering in a paradigm shift in
the way we approach medical interventions [222,223].
The ability to target specific cells, tissues, or organs is a pivotal advancement in
drug-delivery systems. Traditional methods of drug administration often rely on systemic
delivery, where therapeutic agents circulate throughout the entire body, potentially affecting
healthy tissues and organs, leading to adverse side effects. This broad exposure can limit
the dosage and effectiveness of drugs, posing significant challenges to treatment success.
However, biomaterials offer a precision-focused approach. Through careful engineering,
they can be designed to recognize and interact with specific molecular markers, receptors,
or cellular components that are uniquely present on the target cells or tissues. These
engineered biomaterials act as vehicles, shuttling therapeutic agents directly to the intended
site of action, thus concentrating the drug’s effects where it is needed most. This specificity
is achieved through various strategies, such as surface functionalization with ligands,
antibodies, or peptides that bind selectively to the target cells, enabling controlled drug
delivery directly to the disease site.
Cancer therapy is a prime example of how biomaterials are transforming the landscape
of targeted drug delivery. In oncology, the challenge lies in selectively targeting cancer cells
while sparing healthy tissues. Biomaterials, especially nanoparticles and liposomes, have
been engineered to carry chemotherapeutic agents directly to cancer cells. This focused
approach not only maximizes the concentration of the drug at the tumor site but also mini-
mizes the exposure of healthy tissues to toxic chemotherapy drugs, reducing debilitating
side effects such as nausea, hair loss, and immune suppression. Moreover, biomaterials
can be used to create drug-eluting implants or devices designed to target specific organs
or tissues. For instance, drug-eluting stents coated with specialized biomaterials have
been developed to release medication directly into coronary arteries, reducing the risk of
restenosis after angioplasty. Similarly, intravitreal implants release drugs directly into the
eye to treat retinal diseases, circumventing systemic exposure and associated side effects.
In addition to targeted drug delivery, biomaterials have found applications in regen-
erative medicine. Tissue engineering often relies on scaffolds made from biocompatible
materials, which can be engineered to mimic the structure and properties of the target tissue.
These biomaterial scaffolds facilitate the adhesion, proliferation, and differentiation of cells,
ultimately promoting tissue regeneration. Whether it is engineering artificial skin, repairing
damaged cartilage, or growing functional organs, biomaterials serve as the architectural
foundation for these groundbreaking advancements.
The concept of biomaterials for targeted drug delivery extends to gene therapy as
well [224,225]. Here, biomaterials can be designed to transport therapeutic genes to specific
cell types, addressing genetic disorders or promoting tissue repair. By harnessing the
precision of biomaterials, gene therapies can be directed to the precise locations where they
are needed, thus maximizing therapeutic potential while minimizing off-target effects. The
potential of biomaterials for targeted drug delivery and tissue engineering is not limited
to just pharmaceuticals and medical devices. They are increasingly being explored for the
delivery of nucleic acid-based therapies, such as RNA and DNA, which hold immense
promise in treating genetic diseases and a wide range of disorders. By delivering these
therapies directly to the cells or tissues of interest, biomaterials enable the precise and
effective correction of genetic abnormalities while minimizing systemic exposure and
reducing the risk of unintended consequences.
The ability to engineer biomaterials for targeted drug delivery to specific cells, tissues,
or organs represents a monumental shift in modern medicine. This precision-focused
Materials 2024, 17, 456 16 of 27

approach enhances therapeutic efficacy while simultaneously mitigating off-target effects,

ultimately improving patient outcomes, and revolutionizing the way we conceptualize and
practice medical interventions. The continued innovation in biomaterial design and engi-
neering promises even greater strides in the development of highly targeted, personalized
treatments for a wide range of diseases and conditions.

4.4. Stability and Degradation

The concept of designing biomaterials that strike a delicate balance between stability,
controlled drug release, and eventual harmlessness within the body is of paramount
importance in the fields of drug delivery and tissue engineering. Biomaterials serve as
the critical bridge between therapeutic agents and their intended sites of action, and
achieving this equilibrium is essential to ensure the safety and effectiveness of medical
interventions [226,227]. They must maintain stability while releasing drugs, as this stability
ensures the integrity of the drug-delivery system and the controlled release of therapeutic
agents. Stability in this context implies that the biomaterial should preserve its structural
and chemical properties throughout the period of drug delivery. This is particularly vital
for ensuring that the drug remains encapsulated within the biomaterial until it reaches the
target site. Stability safeguards the drug against premature release, preventing any sudden
surges in drug concentration that could lead to adverse effects or treatment failure. The
maintenance of stability in biomaterials involves careful consideration of the material’s
physical and chemical properties. Factors such as mechanical strength, degradation rate,
and porosity are critical in determining how stable the biomaterial remains during drug
delivery. For example, in the case of biodegradable polymers like PLA or PGA, the rate at
which the polymer degrades should be finely tuned to match the desired release kinetics
of the drug. The degradation of the biomaterial is often a controlled process, ensuring it
remains intact until the drug has been delivered.
Controlled drug release, another key aspect of this concept, is fundamental to the
effectiveness of drug-delivery systems. The biomaterial should be designed to release the
drug in a predictable and sustained manner, consistent with the needs of the patient and
the therapeutic agent. Achieving this control involves selecting the appropriate biomaterial
and tailoring its properties to the specific drug and medical condition. Drug-release kinetics
can be modulated through several mechanisms, including diffusion, erosion, and osmosis.
By manipulating these factors, researchers can fine-tune the release profile of the drug,
ensuring it meets the therapeutic requirements. Whether it is a drug-eluting stent that
steadily releases medication over time to prevent restenosis or a tissue-engineered scaffold
that promotes the gradual regeneration of damaged tissues, controlled drug release is
crucial for optimizing treatment outcomes.
The third dimension of this concept involves the biomaterial’s eventual degradation
in the body. In many cases, biomaterials are engineered to be biodegradable, meaning they
are designed to break down harmlessly over time into non-toxic byproducts that can be
metabolized or excreted by the body [228,229]. This degradation process is intricately linked
to the drug-release kinetics. As the biomaterial degrades, it releases the drug, ensuring
that the release profile is consistent with the biomaterial’s breakdown. Biodegradability
is particularly advantageous in scenarios where the implanted biomaterial is no longer
needed once the drug delivery is complete. For example, in orthopedics, biodegradable
bone-fixation devices can be used to hold fractured bones in place during the healing
process. As the bone heals, the biodegradable implant gradually breaks down, eliminating
the need for a second surgical procedure to remove the device. The harmlessness of the
biomaterial’s degradation products is of paramount importance. These byproducts should
not cause harm to the body or induce adverse effects. Biodegradable biomaterials are
designed to degrade into non-toxic compounds that can be easily excreted or metabolized.
This ensures that the biomaterial’s presence in the body is temporary and does not lead to
chronic inflammation or other complications.
Materials 2024, 17, 456 17 of 27

The concept of designing biomaterials that maintain stability while releasing drugs and
eventually degrade harmlessly in the body represents a fundamental pillar of modern drug
delivery and tissue engineering. Striking the right balance between stability and controlled
drug release is essential to ensure the drug’s effectiveness and safety, while engineering
biomaterials to degrade harmlessly minimizes the need for additional medical interventions
to remove implanted devices. This careful orchestration of biomaterial properties not only
enhances patient outcomes but also lays the foundation for innovative and patient-friendly
medical interventions. The continued development and refinement of biomaterials in this
context hold great promise for the future of healthcare.

4.5. Immunogenicity
The significance of minimizing the immune response to biomaterials is highlighted
by immunogenicity. There is a concern about the body’s immune response, which can
result in adverse reactions, inflammatory responses, and rejection [230–233]. This concern
is particularly crucial in biomedical applications, including the development of medical
devices, implants, and drug-delivery systems. The primary goal is to minimize immuno-
genicity to ensure the safety, effectiveness, and long-term success of these interventions..
Biomaterials used in medical applications can often be perceived as foreign entities by the
immune system, triggering a cascade of events that may result in inflammation, foreign
body responses, and, in severe cases, rejection. The immune response can be provoked by
a variety of factors, including the biomaterial’s chemical composition, surface properties,
and its interaction with immune cells. To mitigate these effects, researchers and biomedical
engineers are dedicated to designing biomaterials that minimize their immunogenicity.
One primary focus of minimizing immunogenicity is the selection of biocompatible
biomaterials. These are materials that the body is less likely to recognize as foreign or
harmful. Materials such as biodegradable polymers, medical-grade metals, ceramics,
and certain natural polymers are chosen for their ability to interact harmoniously with
the biological environment, reducing the likelihood of an immune response. In contrast,
non-biocompatible materials or those with surface characteristics that trigger an immune
reaction may result in adverse events and complications. Surface modification is another
key strategy in reducing immunogenicity. By altering the surface properties of biomaterials,
such as using coatings, functionalization, or surface treatments, researchers can make the
material more ‘invisible’ to the immune system. This decreases the chances of the material
triggering an inflammatory response or foreign body reaction. Surface modification can
also facilitate interactions with specific cells or tissues while avoiding immune recognition.
In the context of implantable medical devices and artificial organs, the design and
engineering of biomaterials play a crucial role in minimizing immunogenicity. For in-
stance, cardiac pacemakers and stents made from biocompatible materials like titanium or
medical-grade stainless steel minimize the risk of an immune response. Additionally, the
development of coatings and surface modifications for such devices helps to further reduce
immunogenicity, enhancing their compatibility with the body. Drug-delivery systems
also benefit from strategies that minimize immunogenicity. For instance, liposomes and
nanoparticles used for drug encapsulation are designed to have surfaces that are less likely
to provoke an immune response. These engineered drug carriers are intended to transport
therapeutic agents without initiating an inflammatory reaction or being targeted by the
immune system, ultimately improving drug-delivery efficiency, and reducing the risk of
adverse effects.
In tissue engineering and regenerative medicine, where biomaterials are used to create
scaffolds for cell growth and tissue repair, minimizing immunogenicity is vital. These
scaffolds should not only provide a suitable physical environment for tissue regeneration
but should also avoid immune reactions. To achieve this, biomaterials are carefully selected
and engineered to be biocompatible, thus minimizing the likelihood of immunogenic re-
sponses and promoting successful tissue integration. Furthermore, in the development
of drug and gene therapies, the design of biomaterial carriers is instrumental in reducing
Materials 2024, 17, 456 18 of 27

immunogenicity. The biomaterials used for these therapies are chosen for their biocompati-
bility and designed to protect the therapeutic agents from the immune system, allowing for
precise drug delivery or gene therapy without undesirable immune reactions.
Minimizing the immune response to biomaterials is essential to prevent adverse
reactions and ensure the safety and effectiveness of medical interventions. Through the
careful selection of biocompatible materials and the engineering of surface properties to
reduce recognition by the immune system, researchers are continuously working to advance
the field of biomaterials, making them more compatible with the body and thus contributing
to safer and more successful medical treatments. This focus on immunogenicity represents
a pivotal step in the ongoing evolution of biomedical technology and patient care.
Biomaterials are integral to advancing drug delivery, offering diverse applications
that go beyond conventional uses. They have a transformative impact on cancer treatment,
where biomaterial-based nanoparticles and liposomes can precisely deliver chemotherapeu-
tic agents to malignant cells, minimizing side effects. In managing cardiovascular diseases,
biomaterial-coated drug-eluting stents release medications locally, reducing restenosis
risks. Overcoming the blood–brain barrier, biomaterials aid in targeted drug delivery for
neurodegenerative diseases like Alzheimer’s and Parkinson’s. In vaccine development,
biomaterials optimize immune responses by enabling controlled antigen release. Addition-
ally, biomaterial scaffolds in tissue engineering facilitate cell growth and differentiation,
promising advancements in artificial skin, cartilage repair, and functional organs. In ocular
conditions, sustained release drug-delivery systems enhance the efficacy of treatments for
diseases like glaucoma and macular degeneration. Overall, biomaterials revolutionized the
pain management through the development of localized, sustained-release drug-delivery
systems [234–236]. These systems can be implanted or injected near the source of pain,
ensuring that analgesic medications are delivered directly to the affected area, reducing the
potential for systemic side effects and dependency.
Despite the numerous benefits that biomaterials bring to drug delivery, such as
enhanced drug stability, minimized side effects, and precise administration, persistent
challenges remain. These challenges involve potential toxicity considerations, intricate
manufacturing processes, and the requirement for stringent regulatory approval proce-
dures [237–239]. Moreover, the era of personalized medicine and patient-specific drug-
delivery systems introduces unique complexities and considerations, mandating ongoing
research and innovation in the field. The versatile nature of biomaterials continues to
drive advancements in drug delivery, paving the way for more effective, efficient, and
patient-centered healthcare solutions.

5. Conclusions
Recent biomaterial breakthroughs in drug delivery herald a new era of precision
medicine, with smart biomaterials that are responsive to physiological cues for on-demand
drug release [212,240,241]. Innovations in nanotechnology and gene therapy further en-
hance personalized drug delivery, transforming healthcare. Biomaterials play a large role
in tailoring treatments based on individual genetic profiles and disease characteristics, opti-
mizing outcomes and reducing adverse reactions. They facilitate access to once-inaccessible
areas like the brain, promising significant improvements in conditions such as Alzheimer’s
and specific cancers. Scaffold materials, with intricate microarchitecture, guide tissue
regeneration, while hydrogels provide a supportive environment for stem cell growth and
differentiation [242]. Real-time monitoring and feedback systems in biomaterial-based
drug delivery dynamically adjust drug-release rates, ensuring patients receive precise
doses when needed. The evolving landscape necessitates improved regulatory frameworks
for seamless integration into mainstream healthcare. Biomaterials precisely control drug
release, enhancing efficacy and minimizing side effects. Ongoing research promises ground-
breaking developments, revolutionizing healthcare and defining 21st century medicine
with personalized, targeted drug-delivery solutions. These innovations redefine healthcare
possibilities, offering tailored treatments for individual needs with unparalleled accuracy,
Materials 2024, 17, 456 19 of 27

positioning biomaterials as a beacon of hope for patients and a driving force in medical
practice evolution.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data is contained within the article.
Conflicts of Interest: The author declares no conflicts of interest.

Abbreviation List
Poly(lactic-co-glycolic acid) (PLGA), Hyaluronic Acid (HA), Polyethylene Glycol (PEG), Ex-
tracellular Matrix (ECM), Polycaprolactone (PCL), Polylactic Acid (PLA), Polyglycolic Acid (PGA),
Polymethyl Methacrylate (PMMA), Polyetheretherketone (PEEK), Poly-Lactic Acid (PLA), Poly-
dimethylsiloxane (PDMS), Polystyrene (PS), Polyethylene (PE), Polypropylene (PP), Polycarbonate
(PC), Polyurethane (PU), Magnetic resonance imaging (MRI), Demineralized Bone Matrix (DBM),
iPSCs (Induced Pluripotent Stem Cells), Optical Coherence Tomography (OCT), Virus-like Particles
(VLPs), Lipid Nanoparticles (LNPs), Polyethylene Oxide (PEO), Polyvinyl Alcohol (PVA), and Poly-
butylene Adipate Terephthalate (PBAT).

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