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386 C. Chapa
sustainability lies. While these are not chemical synthesis methods, they can be
treated by chemical methods such as grinding to fine particles. You can also choose
to adapt traditional methods to move towards greener chemistry. In this same sense,
we can highlight that starch is a biodegradable polymer that is obtained in a
sustainable way from various plants, this polymer is a great example of sustainable
methods of obtaining, because it can be obtained even from vegetab
of industrial
tal objectives is obtained as a benefit interesting drug delivery system (Kurczewska
2022). Accordingly, the combination of these materials using environmentally
friendly methods would
even be designed to combine them where properties like crystallinity, particle size,
porosity, morphology, among others that are determinants of drug release efficacy
are controlled, given that pharmaceutical results require their precise control.
processes of food production, in addition to aligning with environmen-
result in highly sustainable solutions. Methodologies can
le waste product
15.7 Properties That the Biomaterial Seeks to Be a Drug
Delivery System
It is well recognized that individual materials can act collaboratively, and the
properties of the combined material can act in concordance. In that sense, it is
expected that hydroxyapatite combined with starch will offer synergistic properties
for drug delivery systems whose final properties will be a result of a mutual
interaction of both materials. In principle, both materials can present to a greater
or lesser extent crystallinity that would affect the adsorption capacity or encapsulation efficiency and the rate of drug release or release kinetics. We could be in the
presence of a hydroxyapatite with high crystallinity that presents a slower and
sustained release, which is not necessarily detrimental if what is sought is a therapeutic application by sustained release action over time. Particle size is also a
property that should not be left to chance because it plays an important role. In
general, it has been accepted that smaller particles have a larger surface area, which
can be used to increase the absorption rate of the drug. As for starch, we cannot fail
to mention that its structure is anything but consistent between sources, let alone the
degree of cross-linking, which can influence the release kinetics. However, by
predictably characterizing the starch to be worked with, we could know if it has a
denser and more cross-linked structure which would be beneficial in slowing down
the release of the drug for sustained release (Lukova et al. 2023).
Therefore,
starch matrices requires control of several other important parameters such as size
and morphology, which ultimately affect the encapsulation efficiency and drug
release kinetics. Particle size and morphology are both parameters that can be
tunable during synthesis and can definitely impact on the biodistribution and bioavailability of the drug (Ren et al. 2021). To be precise, encapsulation efficiency
refers to the amount of drug that can be incorporated into the matrix and is a key
factor in ensuring adequate therapeutic doses, while release kinetics, on the other
hand, determines the rate at which the drug is released from the material. All reports
to achieve drug encapsulation in hydroxyapatite in combination with
15 Hydroxyapatite-Starch-Based Sustainable Biomaterials 387
of release systems using this combination, and others, should report these parameters
and relate them to the properties we have mentioned, in order to be able to compare
and make decisions to obtain the biomaterial that is most appropriate for the
treatment of chronic diseases that require sustained release.
Consequently, among the properties that the combination of these biomaterials
should be carefully observed are:
(a) Crystallinity: To call crystallinity in both hydroxyapatite and starch is to refer
to one of the properties that both shares. Crystallinity, as is well known, affects
mechanical strength, degradation rate, interaction with surrounding water
molecules. On the one hand, high crystallinity in hydroxyapatite would result
in high stability and bioactivity, although it is unlikely to relate bioactivity to
drug release, it is plausible that crystallinity also determines prolonged drug
release. On the other hand, crystallinity in starch is associated with amylopectin
containing and the amorphous phase with amylose. And given that the content
of both polymers depends on the nature of the source, this will have a decisive
influence on the ability to form stable and uniform matrices for drug
encapsulation.
(b) Particle size:
Particle
size is closely related to drug loading capacity and release
kinetics. Smaller particles typically have a larger surface area for drug adsorption, leading to higher drug loading efficiency. Even the particle size distribution
influences the release profile of encapsulated drugs. In the case of hydroxyapatite nanoparticles, they can be obtained in various sizes and sieved to reduce
their size distribution, aiming for smaller particle sizes to be associated with
higher drug loading and capacity for controlled release. It is difficult to find
reports of starch particle sizes in the nanometer scale when they are obtained
from their sources, regularly the materials are microstructured. But through
physical or chemical processes, particle sizes in the nanometer scale can be
achieved.
(c)
Porosity: Matr
ices formed by polymers that produce porous structures in which
the drug is disseminated allow the drug to infiltrate into the pores of the matrix
system, followed by a slow diffusion step of the drugs in the channels. The ratelimiting step in drug release from this type of system is the penetration of the
dissolution liquid into the matrix, with water permeation promoted by the
addition of wetting agents. The increased surface area resulting from the porosity of the nanohydroxyapatite may contribute to the ability of a matrix to load
drugs. As for starch, in addition to the structural and biological properties
already mentioned, it is also possible to functionalize its surface, making it
more efficient and selective as a drug-carrying matrix, since the anchoring of
functional groups on porous matrices causes changes in pore size and drugsubstrate interaction, resulting in lower drug loading and a slower release rate,
which is desirable. Not to be omitted that the release of the active ingredient is
essentially controlled by diffusion mechanisms through the pores or by erosion,
in addition to hydrolysis in the case of hydrophilic polymers with one or the
other mechanism prevailing depending on the properties of the drug.
388 C. Chapa
15.8 Hydroxyapatite-Starch Based Drug Delivery Systems
In the existing literature there are formulations that already incorporate hydroxyapatite and starch for drug delivery. Table
recent publications where several formulations incorporating hydroxyapatite-starch
based materials were developed to assess their efficacy in drug delivery systems
covering from antibiotics to glucocoticoids. As can be seen, the frameworks were
designed to improve specific properties of the drug release studies, in general the
release profiles were better in the systems that took advantage of the unique
properties of the composites.
It is clear from the data presented in Table 15.1 that a ternary mixture of
polylactic acid (PLA), starch and poly ε-caprolactone (PCL) was used alongside
nanohydroxyapatite (nHA) by fusion. Although the resulting nanocomposite does
not exclusively combine hydroxyapatite with starch, its mention in this discussion is
not misplaced, as it should be noted that the composite with 3% nHA demonstrated
better hydrolytic degradation, higher hydrophilicity, greater antibacterial activity and
optimized triclosan release profiles (Davachi et al. 2017). Triclosan is an antiseptic
agent which belongs to the chemical group of polychlorinated phenoxyphenols. It is
effective against gram-negative and gram-positive bacteria, fungi and molds. It is a
regulated ingredient commonly found in medicines, soaps, lotions, deodorants and
toothpastes.
Yet another formulation hydroxyapatite was combined with β-C D to carry
dexamethasone, a hydrophobic drug. Again, hydroxyapatite is not directly combi ned
with starch, but this example is particularly interesting because cyclodextrins are
produced from starch by enzymatic conversion, which is why they are sometimes
15.1 presents a summarized overview of
Table 15.1 Formulations of drug delivery system based on hydroxyapatite combined with starch
Formulation Drug Results Ref.
Polylactic acid/starch/poly
ε-caprolactone, mixed with
nano hydroxyapatite (nHA)
via melt blending
Hydroxyapatite (HA)/
Cyclodextrin (β-CD)
nanocomposite
Dispersion of hydroxyapatite
into urea and thermoplastic
starch at
HA and
phosphate based porous
scaffolds formed by applying
together starch consolidation
with foaming method
nanoscale
pure β-
tri calcium
Triclosan 3% nHA increases material’s
Dexamethasone The release of dexamethasone
Urea (fertilizer) Study
Ceftriaxone HAp exhibited better drug
degradation, antibacterial
action, and drug release.
from β-CD/HA was about
pH 5.3
4.6% at
pH 7.4.
shows breaking up
hydroxyapatite particles and
dispersing them in watersoluble materials improves
how well phosphate releases
release profile than β- tri
calcium phosphate when drug
was used alone
and 18.7% at
Davachi
et al.
(2017)
Salimi
and
Molaei
(2021)
Giroto
et al.
(2015)
Kundu
et al.
(2010)
15 Hydroxyapatite-Starch-Based Sustainable Biomaterials 389
also called “cycloamylases”. These compounds are used in food, pharmaceuticals,
drug delivery systems. Moreover, in this work the nanocomposite showed
pH-sensitive drug release, with a release of 4.6% at pH 5.3 and 18.7% at pH 7.4,
consequently, it is highlighted that the system functions as a pH-sensitive sustainable
release carrier for the hydrophobic Drug (Salimi and Molaei
is a
drug belonging to the glucocorticoid class. It mainly can treat diseases of
). Dexamethasone
2021
rheumatic, immune, skin, ocular, endocrine, pulmonary, blood, gastrointestinal,
neurological and neoplastic origin. Dexamethasone has an anti-inflammatory action
due to the inhibition of phospholipase A2, which causes the inhibition of the entire
arachidonic acid cascade, impeding the formation of prostaglandin, thromboxane
and leukotrienes. In addition, they al
leukocytes,
thus reducing the release of cytokines at the site of inflammation,
so act by reducing the migration and adhesion of
resulting in immunosuppressive activity.
In a different approach, the incorporation of hydroxyapatite nanoparticles into
thermoplastic starch matrices was explored by the authors. The thermoplastic starch
has an amylose content higher than 70% and are gelatinized vegetable starch based.
With the use of specific plasticizing solvents, can produce thermoplastic materials
with good performance properties and inherent biodegradability. The starch is
typically plasticized, unstructured or blended with other materials to form useful
mechanical properties. Although generally, the applications of thermoplastic starch
polymers are generally films, such as shopping bags, bread bags, bait bags,
wrapping, “washable” medical device backing material and mulch film, their inclusion in a delivery system, not for drugs, but for compounds of interest is noteworthy
as well as sustainable. The biodegradation of starch-based polymers is the result of
an enzymatic attack on the glycosidic bonds between the carbohydrate groups
leading to a reduction in chain length and the cleavage of the carbohydrate units
into monosaccharides, disaccharides and oligosaccharides, which are readily utilized
in biochemical pathways. The work aimed to improve the solubility of poorly
soluble phosphate phases. It was revealed that the dispersion of HAp within the
matrices improved phosphate release and the influence of hydroxyapatite particles
and their dispersion in water soluble materials was demonstrated to significantly
improve phosphate release. This improved release profile heralds that the combined
material increases fert ilizer efficacy by achieving a more sustained release of
nutrients (Giroto et al. 2015).
Previously,
the use of porous hydroxyapatite (HAp) and β-tricalcium phosphate
(β-TCP) scaffolds fabricated by a starch consolidation and foaming method had
already been reported. For that reason, this study is also incorporated in this analysis,
since it combines both materials that we have been mentioning, this time the study
was about the local administration of ceftriaxone in the treatment of osteomyelitis As
mentioned before, the porosity of the materials is one of the main proper ties to be
controlled and in this study the importance of high porosity and interconnectivity in
the release of the drug was highlighted. Ceftriaxone was incorporated into the
scaffolds and the results showed that hydroxyapatite provided a better drug release
profile than β-TCP when used alone (Kundu et al.
010). Ceftriaxone is a broad-
2
spectrum injectable antibiotic used to eliminate excess bacteria in the body and can
390 C. Chapa
therefore be used to treat various types of infections, from sexually transmitted
infections to skin infections, pneumonia and even meningitis.
15.9 Strategies for Drug Incorporation
in Hydroxyapatite-Starch Compounds
Studies where drug incorporation into hydroxyapatite (HA)-starch composites will
certainly continue to appear in the literature in the coming years. Conducting these
investigations would involve various strategies designed to optimize drug loading
and release profiles that take into account the properties of the composite. For
example, the common approach of co-precipitation would incorporate drugs during
the synthesis of the starch and HA composite. With this method, a uniform distribution of the drug within the composite matrix would be sought. Perhaps the most
obvious or most commonly used strategy is surface adsorption, whereby drugs are
adsorbed on the surface of the preformed hydroxyapatite particles combined with
starch through weak bonds. This technique would be particularly useful for drugs
that have a strong affinity for the starch or hydroxyapatite surface. On the other hand,
encapsulation techniques should be considered, the starch polymer lends itself to
form a layer around the hydroxyapatite particles containing adsorbed drug or the two
separately. This method of encapsulation can protect drugs from premature degradation and allow a sustained release over time, the role of hydroxyapatite would also
play to that end.
most, if not all, nanomedicine drug delivery systems, the kinetics of drug
As in
release from HA starch composites will be influenced by several factors, including as
mentioned above the porosity and crystallinity of the composite, the properties of the
drug and the interaction between the drug and the composite matrix. Drug release is
anticipated to occur through a combination of diffusion, degradation and dissolution
mechanisms. Initially, a burst release would occur due to the release of adsorbed
drug at or near the surface of the composite, this is usually seen by a steep slope in
graphs plotting the amount of drug released as a function of time. This first phase is
usually followed by a more sustained release phase in which the drug encapsulated
within the matrix is gradually released as the compound degrades, keep in mind that
it is the starch that is expected to degrade, the hydroxyapatite less often. Again it is
important to emphasize that higher porosity allows for higher drug loading and
facilitates faster drug diffusion, but it will also depend on several properties such as
the molecular mass of the drug and stereochemistry. Returning to the rate of starch
degradation, it must be said that this will affect drug release as the starch degrades in
compartments where amylase enzymes are presen t, when degraded it would create
channels that allow drug diffusion, contributing to the sustained release phase, these
release profiles could present interesting kinetics.
15 Hydroxyapatite-Starch-Based Sustainable Biomaterials 391
15.10 Future Perspectives and Challenges
Despite their promising potential, hydroxyapatite composites in combination with
starch face several limitations in drug delivery applications. An important limitation
is the chemical resistance of hydroxyapatite. While hydroxyapatite provides some
structural integrity, routes of administration must be chosen in accordance with the
idea that hydroxyapatite is unlikely to degrade under physiological conditions.
While the incorporation of starch may provide elements of degradability, the overall
strength of the composite in particular would be determined by the persistence of the
hydroxyapatite, which is perhaps why studies are focusing on bone or dental
applications. In any case, achieving a balance between the degradation of the starch
component and the stability of the hydroxyapatite is a fundamental limitation to be
overcome in the future to advance this topic. To address these limitations,
researchers can resort to surface modification techniques, size control, etc. to promote better properties.
15.11 Conclusion
In conclusion, hydroxyapatite composites combined with starch definitely represent
a sustainable approach to drug delivery. However, their potential application as a
nanomedicine system for controlled drug release is still not being harnessed for the
potentially wide range of medical applications that could benefit from the combination of biocompatibility, bioactivity and other capabilities. What it is clear is that
innovations in composite formulation, manufacturing techniques will further
enhance their functionality and versatility by adopting green methods so that, as
these materials continue to evolve, sustainable options with great potential for drug
delivery will offer efficient and affordable solutions to complex medical challenges.
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