polymers

Review
Embracing Sustainability: The World of Bio-Based Polymers in a
Mini Review
Grazia Isa C. Righetti * , Filippo Faedi and Antonino Famulari *

Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano,
Piazza Leonardo da Vinci 32, 20133 Milano, Italy
* Correspondence: [email protected] (G.I.C.R.); [email protected] (A.F.)

Abstract: The proliferation of polymer science and technology in recent decades has been remarkable,
with synthetic polymers derived predominantly from petroleum-based sources dominating the
market. However, concerns about their environmental impacts and the finite nature of fossil resources
have sparked interest in sustainable alternatives. Bio-based polymers, derived from renewable
sources such as plants and microbes, offer promise in addressing these challenges. This review
provides an overview of bio-based polymers, discussing their production methods, properties, and
potential applications. Specifically, it explores prominent examples including polylactic acid (PLA),
polyhydroxyalkanoates (PHAs), and polyhydroxy polyamides (PHPAs). Despite their current limited
market share, the growing awareness of environmental issues and advancements in technology are
driving increased demand for bio-based polymers, positioning them as essential components in the
transition towards a more sustainable future.

Keywords: bio-based polymers; polymers; sustainable materials; renewable sources; polymeric materials

1. Introduction
The interest in polymer science and technology has witnessed an unprecedented
growth over the past few decades, leading to rapid advancements in the development of
Citation: Righetti, G.I.C.; Faedi, F.; polymers and plastics. Throughout the 20th century, the polymer industry was heavily
Famulari, A. Embracing Sustainability: reliant on petroleum-related chemistry, refineries, and processes. The petrochemical boom
The World of Bio-Based Polymers in a in the latter half of the century played a pivotal role in propelling the progress of the
Mini Review. Polymers 2024, 16, 950. chemical sciences, experiencing unparalleled growth in the organic chemical industry.
https://doi.org/10.3390/
Despite ongoing debates about the detrimental environmental impact of petroleum-
polym16070950
related processes, industries hesitated to alter their raw materials or methodologies until
Academic Editors: Stefano Farris the situation reached a critical juncture. Notably, this era saw the discovery of various
and Masoud Ghaani monomers for polymerizations, propelling synthetic polymers to a prominent position in
the global market, as they could be utilized in the production of a wide array of every-
Received: 28 February 2024
day commodities.
Revised: 25 March 2024
This remarkable scientific and technological upswing led to the gradual displacement
Accepted: 28 March 2024
Published: 30 March 2024
of naturally occurring polymers by their synthetic counterparts. This choice was primarily
driven by economic considerations, as the cost of oil was significantly lower than the
processing of natural fibers at that time. Although polymers derived from renewable
sources continued to exist, they played a minor role due to limited investments compared
Copyright: © 2024 by the authors. to the substantial funds allocated to petrochemistry.
Licensee MDPI, Basel, Switzerland. However, the polymer industry copes with two significant challenges: global warming
This article is an open access article and the depletion of fossil resources. A potential solution to address these issues involves
distributed under the terms and exploring the use of renewable sources instead of fossil-based ones. Moreover, the decreased
conditions of the Creative Commons availability of fossil resources resulted in a surge in market prices, exacerbated by the fact
Attribution (CC BY) license (https://
that oil is not universally accessible and requires certain states to be subjected to others. In
creativecommons.org/licenses/by/
contrast, renewable resources are globally shared, making them highly valuable [1,2].
4.0/).

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Polymers 2024, 16, 950 2 of 23

In the ever-evolving landscape of polymers for materials science, the quest for sustain-
able alternatives has become imperative. In light of the growing concerns and an increased
awareness of the environmental impact of traditional plastics, researchers are turning
their attention to bio-based polymers as a promising solution. The urgency to reduce the
consumption of fossil fuels, together with the negative impact of plastic pollution on the
environment, has exponentially increased the interest in these alternative materials. As
we try to face the challenges of a global environmental crisis, the significance of bio-based
polymers extends beyond their material properties. Their potential to mitigate carbon
emissions, reduce plastic pollution, and contribute to a circular economy underscores their
pivotal role in building a sustainable future.
Bio-based polymers are derived from renewable resources such as plants, microbes,
and agricultural or forestry feedstock and represent a paradigm shift in the pursuit of
eco-friendly materials. They can be produced from the raw sources through chemical,
physical, or biochemical transformations, and due to the sustainable nature of the starting
material, bio-based polymers offer several advantages such as a reduced carbon footprint
and the potential for higher biodegradability [3,4]. Even if it was logical to assume that
polymers crafted from renewable and frequently biodegradable sources would possess
biodegradable properties as well, this feature is not always assured. Variations in functional
groups, crosslink density, and the inclusion of non-biodegradable co-monomers through
copolymerization may lead to materials that do not necessarily demonstrate substantial
biodegradability [5,6]. As the terms “biodegradable” and “bio-based” are often mentioned
in the literature, it is crucial to underline the key difference between these two types of
polymers. A biodegradable polymer is defined as a material able to undergo degradation
and deterioration. The biodegradation of a polymer (bio-based or synthetic) is defined
as the chemical decomposition process of the substance into environmentally friendly
compounds [7]. After a first fragmentation step of the high molecular mass (HMW)
polymer to a lower molecular mass (LMW) group of chains [8,9], the final degradation is
dependent on microorganisms which, based on the environment (aerobic or anaerobic),
will convert the substances mainly into CO2 , H2 O, and CH4 [10]. On the other hand,
bio-based polymers are defined by IUPAC as “composed or derived in whole or in part of
a biological product issued from biomass (including plant, animal, and marine or forestry
materials)” [11].
The primary advantage of bio-based polymers relies on substituting non-renewable
resources with renewable carbon sourced from biomass, a crucial step in achieving sus-
tainability and promoting a climate-friendly plastics industry. Another key benefit is that
biodegradable bio-based polymers constitute roughly a quarter of all bio-based polymers
(depending on environmental conditions). These next-generation polymers might be the
key to a lower reliance on fossil fuels, offering a potential solution to the problem of
uncollected and unprocessed plastics in the environment [12,13].
Bio-based polymers still hold just a small fraction of the market, accounting for 0.5% of
the overall global plastic production and 1.0% of the European market in 2023 (Figure 1) [14].
However, the global market request is estimated to expand at a compound annual growth
rate of 18.8% from 2023 to 2030 [15].
Despite the currently low market fraction occupied by bio-based polymers, their
crucial role in shifting plastic production towards a greener and more sustainable direction
is underlined by the growing interest among researchers in both academia and industry.
This is evident not only in the increasing number of scientific articles and citations dedicated
to this subject (Figure 2) but also in the wide application of those polymers in different
fields (Figure 3).
16, x FOR Polymers
PEER REVIEW
2024, 16, 950 3 of 25
3 of 23

Figure 1. Plastic production in 2023:

Figure 1. Plastic (a) globalinplastic
production production,
2023: (a) (b)production,
global plastic European(b) plastic production,
European plastic production,
(c) bio-based plastic
(c)production per country
bio-based plastic in Europe.
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PlasticEurope [12].

This mini-review
Despite the currently low market aims to provide
fraction occupied an by
overview
bio-basedon three important
polymers, theirbio-based
cru- poly-
mers: (a) polylactic acid (PLA), (b) polyhydroxy alkanoates (PHA),
cial role in shifting plastic production towards a greener and more sustainable direction and (c) polyhydroxy
polyamides (PHPAs).
is underlined by the growing interest among researchers in both academia and industry.
These three polymers were chosen due to their importance among all the biobased
This is evident not only in In
polymers. thefact,
increasing
polylacticnumber of scientific
acid (PLA) articles alkanoates
and polyhydroxy and citations
(PHA)dedi-
are the most-
cated to this subject (Figure
studied 2) butpolymeric
bio-based also in the wide application
materials due to their of those polymers
potential in dif-
to replace petroleum-based
ferent fields (Figure 3).
polymeric materials thanks to their peculiar properties. Their importance is also underlined
by the fact that they have already found applications in many fields, ranging from packag-
ing to biomedical fields [16]. On the other hand, polyhydroxy polyamides (PHPAs) have
also gained increasing attention with the aim of synthetizing new, more hydrophilic and
degradable polymeric materials [17]. What makes this class of polymers highly attractive
is the nature of the dicarboxylic acid employed, which is a natural carbohydrate-based
monomeric building block that displays peculiar structural features (e.g., stereochemistry)
that can help tune the polyamide’s final properties [18].
Polymers 2024, 16, x FOR PEER REVIEW
NUMBER OF DOCUMENTS ON BIO- 4 of 25
Polymers 2024, 16, 950
BASED POLYMERS 4 of 23

140,000
OF DOCUMENTS

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NUMBER OF

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0 Figure 2. Total number of documents produced on bio-based polymers per year from 1995 to 2003,
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
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including both articles and patents. Dimension AI was used as a tool to retrieve the total number of
documents per year on the given topic.
YEAR
This mini-review aims to provide an overview on three important bio-based poly-
Figure 2. Total number of documents produced on bio-based polymers per year from 1995 to 2003,
mers: 2.
Figure
(a)Total
polylactic acid (PLA), (b)produced
polyhydroxy alkanoates (PHA), year
and from
(c) polyhydroxy
including both number of documents
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polyamides
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articles and patents. Dimension AI was used as a tool to retrieve the total number of
documents per year on the given topic.
documents per year on the given topic.

This mini-review aims to provide an overview on three important bio-based poly-

mers: (a) polylactic acid (PLA), (b) polyhydroxy alkanoates (PHA), and (c) polyhydroxy
polyamides (PHPAs).

Figure 3. Examples of some applications of biopolymers and bio-based polymers.

polymers.

2. Bio-Based Polymers
These three polymers were chosen due to their importance among all the biobased
2.1. Polylactic
polymers. Acid polylactic acid (PLA) and polyhydroxy alkanoates (PHA) are the most-
In fact,
Polylactic acid (PLA), a biodegradable aliphatic polyester, has been known since 1845
Figure Theophile-Jules
when Pelouze
3. Examples of some first synthesized
applications it [19].
of biopolymers It has been
and bio-based extensively studied in
polymers.
the past 20–25 years due to its exceptional properties, such as its high biodegradability and
biocompatibility.
These three polymers were chosen due to their importance among all the biobased
PLA is
polymers. Incomposed of lactic
fact, polylactic acidacid
(PLA)as its
andfundamental
polyhydroxybuilding block.
alkanoates Thisare
(PHA) monomer is
the most-
a hydroxyl carboxylic acid that can be obtained from renewable sources like corn starch
 Polymers 2024, 16, 950 5 of 23

(via fermentation processes) or sugarcane. Even if various renewable resources can be

employed, corn stands out, as it offers the advantage of yielding a high-quality feedstock
for fermentation, resulting in the production of high-purity lactic acid. Depending on the
microbial strain utilized in the fermentation process, both L-lactic acid and D-lactic can be
obtained [20].

2.1.1. Polylactic Acid Synthesis

PLA can be synthetized via direct polymerization of lactic acid or via ring-opening
polymerization (ROP) of the lactide monomer, where the lactide is the cyclic dimer of
lactic acid (Scheme 1). Typically, the polycondensation process is associated with a low-
molecular-weight polymeric product due to water formation associated with the lactic acid
condensation process causing the degradation of the forming polymeric chain itself. Water
removal systems and protocols utilizing high temperatures in the presence of catalysts have
been proposed to attain higher degrees of polymerization in the production of polylactic
acid (PLA) [21]. Nevertheless, these approaches still face limitations, primarily stemming
Polymers 2024, 16, x FOR PEER REVIEW 6 of 2
from challenges in effectively removing water as the degree of polymerization (DP) of PLA
increases, and from material degradation issues at elevated temperatures [22].

O O

OH OH
OH OH

L-Lactic acid D-Lactic acid

O O O O O O

O O O O O O

(a) L-Lactide D-Lactide meso-Lactide

O
O O
OH
OH Dimerization O O
- H2O
Lactic acid Lactide

Polycondensation Ring-opening
polymerization
- H2O
(ROP)

O
O OH
HO O
n
O O

(b) Polylactic acid

Scheme1.1.(a)(a)
Scheme optical monomers
optical of lactic
monomers acid and
of lactic acidstereoisomers of lactide;
and stereoisomers of(b) formation
lactide; of polylactic
(b) formation of polylac
acid via polycondensation and ring-opening polymerization.
tic acid via polycondensation and ring-opening polymerization.
The current preferred synthetic pathway for producing polylactic acid (PLA) is ring-
2.1.2. Polylactic
opening Acid: Physical
polymerization. This methodProperties
offers enhanced control over various reaction param-
Extensive
eters such research has
as polydispersity, focused weight,
molecular on understanding the properties
and stereochemistry. Notably,of polylactic
ring-openingacid (PLA)
polymerization allows for precise control over the insertion of lactide monomers,
These properties are influenced by factors such as stereochemistry, processing temperature and the
stereochemistry
annealing time,of PLA
and can be easily
molecular manipulated
weight by polymerizing
(Mw). Specifically, d, l, or meso-lactide
the stereochemistry and thermal his
monomers [23]. The ability to control and modulate stereochemistry is pivotal, as it
tory of PLA have a direct impact on its crystallinity, which in turn affects its properties.enables
the production of polymers with markedly different characteristics. From this perspective,
Crystallinity, which refers to the proportion of crystalline regions in the polyme
compared to the amorphous content, plays a crucial role in determining various proper
ties of PLA. These properties include hardness, modulus, tensile strength, stiffness, creas
resistance, and melting points (the values of some of these parameters are reported in
Table 1, with those of polypropylene and polyethylene provided for a comparison with
Polymers 2024, 16, 950 6 of 23

the investigation of metal complexes as catalysts in lactide polymerization via coordination–

insertion mechanisms has experienced a surge in interest over the past decade. While tin
(II) bis(2-ethylhexanoate), commonly referred to as Sn(Oct)2 , remains the most-utilized
catalyst for industrial PLA synthesis, other examples such as aluminum, zinc, magnesium,
and calcium have also gained widespread usage [24–27].

2.1.2. Polylactic Acid: Physical Properties

Extensive research has focused on understanding the properties of polylactic acid
(PLA). These properties are influenced by factors such as stereochemistry, processing
temperature, annealing time, and molecular weight (Mw). Specifically, the stereochemistry
and thermal history of PLA have a direct impact on its crystallinity, which in turn affects
its properties.
Crystallinity, which refers to the proportion of crystalline regions in the polymer
compared to the amorphous content, plays a crucial role in determining various properties
of PLA. These properties include hardness, modulus, tensile strength, stiffness, crease
resistance, and melting points (the values of some of these parameters are reported in
Table 1, with those of polypropylene and polyethylene provided for a comparison with
synthetic non-bio-based polymers). The degree of crystallinity significantly influences the
mechanical, thermal, and processing characteristics of PLA, making it a key parameter in
understanding and optimizing PLA-based materials for diverse applications.

Table 1. Comparison between the physical properties of PLA [28–30], polypropylene (PP) [31–34],
and high-density polyethylene (HDPE) [34–38].

Type of Polymer
Properties
PP
PLA PLLA PDLLA HDPE
Homopolymer
Polymer density—ρ (g/cm3 ) 1.21–1.25 1.24–1.30 1.25–1.27 0.91–0.94 0.80–1.80
Tensil strength—σ (MPa) 21–60 15.5–150 27.6–50 22–34.4 11.6–40
Young’s modulus—E (GPa) 0.35–3.5 2.7–4.14 1–3.45 0.545 0.30–1.30
Strain—ε (%) 2.5–6 3.0–10.0 2.0–10.0 // 20
Elongation at break (%) 10 // // 3–700 3.5–800
Glass transition
45–60 55–65 50–60 −25 −120
temperature—Tg (◦ C)
Melting temperature—Tm (◦ C) 150–162 170–220 n.a. 1 160–166 127–255
Crystallinity (%) 42 // // 30–60 70
1 n.a.—not applicable: amorphous material does not have a well-defined melting point.

PLA is renowned for its exceptional optical properties and high tensile strength. How-
ever, its versatility and potential applications might be compromised by its rigidity and
brittleness at room temperature; characteristics that stem from its glass transition tempera-
ture (Tg ) of approximately 55 ◦ C. PLA might meet the mechanical property requirements for
most rigid objects, but it needs to be plasticized when it comes to its applications, especially
as films in the packaging industry. Plasticizers play a vital role in enhancing the processabil-
ity, flexibility, and ductility of polymers. In the case of semi-crystalline polymers like PLA,
an effective plasticizer needs to not only reduce the glass transition temperature (Tg ) but also
depress the melting temperature (Tm ) and overall crystallinity [30,39,40]. Different kinds
of molecules are reported in the literature as plasticizing agents for PLA. Low-molecular-
weight agents such as glycerol, sorbitol, bishydroxymethyl malonate (DBM), adipates and
citrates [41], vegetable oils derivatives [42,43], and 10,16-dihydroxy hexadecenoic acid and
its derivatives [29] have been tested, but these molecules showed a high mobility inside
the PLA matrix due to their low molecular weight [44]. In order to reduce the plasticizer
migration phenomena, blending PLA with higher-molecular-weight compounds such as
polyethylene glycol (PEG) [45,46], poly(propylene) glycol (PPG) [47], or poly(diethylene
adipate) (PDEA) [48] has emerged as an appealing solution. Some starch-blended PLA mix-
tures like Mater-Bi (Novamont, Novara, Italy) and Bioplast (Biotec, Emmerich am Rhein,
Germany) [49] have also reached the market. Despite the wide range of plasticizer choices
Polymers 2024, 16, 950 7 of 23

offered by the ever-growing scientific literature, this is often constrained by legislative or

technical requirements that are specific to their application, especially in the medical and
food industries [44,46,50]. This limitation makes the selection process more challenging.
In fact, the plasticizer used for PLA must meet stringent criteria such as biodegradability,
non-toxicity, and/or biocompatibility. As a result, the most common plasticizers used for
PLA are low-molecular-weight polyethylene glycols (PEGs) [30,40,45,46].

2.1.3. Polylactic Acid Applications

Currently, PLA-based products have entered the market with various applications,
ranging from drug carriers, temporary implants, and bone-fixing elements to degradable
dishes and packaging. PLA, as a highly versatile and environmentally friendly polymer,
possesses renewability, biodegradability, transparency, colorlessness, processability, and
mechanical properties, making it increasingly interesting as a substitute polymer for those
products where recycling, reuse, and product recovery of the materials are not feasible [51].
As the production costs for PLA manufacturing processes decrease, the potential for PLA
to be utilized in a broad array of products continues to grow.
One of the largest potential application areas for PLA is in fibers, where the first
commercial success as a fiber material was in the form of resorbable sutures [23]. Since
then, PLA has been extensively studied, especially for its potential use in other medical
applications due to its bioresorbability and biocompatible properties in the human body. In
this sector, PLA is employed not only in wound management but also to produce resorbable
stents [52], as encapsulation systems to enhance target-specific drug delivery [53–58], in the
orthopedic field as fracture fixation systems and as temporary fillings in facial reconstructive
surgery [59], and in tissue engineering and regenerative medicine fields [30,60,61].
The second-largest application for PLA is in the production of films, particularly in
the food packaging industry. PLA films are prized for their transparency and excellent
deadfold or twist retention properties, making them increasingly sought after as a green
alternative in food packaging due to their biodegradability. In the packaging sector, PLA
finds applications ranging from containers for fresh produce to disposable cutlery and
drinking cups. While PLA presents several advantages, such as biodegradability, it also
poses challenges that need to be addressed. These include inferior moisture barrier prop-
erties and brittleness [62]. To overcome these challenges, various approaches are being
explored, including coatings, lamination, blends with other polymers, and chemical or
physical modifications [63]. However, achieving a balance between stiffness and toughness
while maintaining a high biobased content remains a significant challenge. Strategies such
as plasticizing PLA with its own monomers or blending it with other polymers have been
attempted, but they often encounter issues such as phase separation [24,64].
PLA is a good candidate material for 3D printing technology, and in the last three years,
many investigations have been focused on tuning its properties for this application [65].
Melt extrusion (MEX) is the most-used 3D molding method, and it imposes some require-
ments to the molding material such as a low viscosity, sufficient adhesion, robustness,
and stability. PLA as a 3D printing material partially meets these requirements, but it
presents some defects such as a poor high-temperature resistance, brittleness, and low
impact resistance. The performance of PLA’s extruded filament can be improved by adding
auxiliary material and changing the processing parameters. The research in this field has
focused on changing the mechanical properties of PLA filaments and improving their
printing performance. One promising root to make PLA suitable for 3D printing is to
add natural fillers to the polymers, such as calcined shell particles (CSh), straw meal, and
poplar fibers. The resulting materials are completely biodegradable and result in a higher
tensile strength of the polymers [66–68]. Copper and lignin are used as fillers for impact
resistance enhancements. The addition of lignin microspheres resulted in an increase in
impact strength of 100% [69], and Cu-modified PLA achieved remarkable results in impact
resistance tests as well [70]. Regarding the change in processing parameters, Fontana et al.
analyzed the effects of layer height (LH) and fill rate on the ultimate tensile strength (UTS)
Polymers 2024, 16, 950 8 of 23

values of 3D-printed tensile specimens of Makerbot PLA rigid materials [71,72]. The data
analysis revealed that the LH had a more prominent effect on the mechanical strength than
the fill rate.
The inherent ignitability properties of neat PLA restrict its application [71,72]. A way
to improve PLA’s fire safety is to add flame retardants to the neat polymers. Among them,
the most successful have been intumescent flame retardants (IFR), P/N synergistic systems,
metal oxides, hydroxides, and nanomaterials [73–75].
Intumescent flame retardants (IFR) proved to be very efficient, environmentally
friendly, and also capable of increasing the mechanical properties of PLA [76]. Recently, a
novel bio-based IFR with a nanosheet structure, PP-Fe, was fabricated using self-assembly
technology. The new material presented an outstanding increase in fire safety and UV
resistance. For fire safety, introduction of 20.0 wt% PP-Fe nanosheets to PLA resulted in
significant reductions in the PHRRc (72.7%), THRc (41.6%), and TSP (64.7%) values in
the CCT and achieved a UL-94 V-0 rating with an LOI of 31.2%. The UPF value of the
PLA/20PP-Fe composite was 120%, categorized as excellent UV shielding [77].
Despite these challenges, PLA holds promise as a future material for eco-friendly food
packaging, and ongoing research and innovation in this field are expected to lead to further
improvements and applications.

2.2. Polyhydroxy Alcanoates

Poly(hydroxyalkanoates) (PHAs) represent a class of biopolymers prized for their
biodegradability and their ability to be derived from natural resources. Falling under the
umbrella of aliphatic polyesters, PHAs have gained significant attention from both the
scientific and industrial sectors owing to their potential as biomaterials. In fact, due to
the combination of their innate biodegradability, natural origin, functional versatility, and
compatibility with biological systems and their mechanical and thermal properties, they are
viewed as promising alternatives to petroleum-based plastics [78]. Notably, PHA stands
out as an ideal candidate due to its ability to form small pores, facilitating efficient recycling
and boasting a high volume-to-surface ratio [79].
PHA, comprised of hydroxyalkanoic acid monomers, owes its uniqueness primarily
to its fascinating production process. This process is a captivating biological phenomenon
orchestrated by a diverse array of microorganisms such as Alcaligenes latus, Azobacter
vinelandii, Bacillus megaterium, Cupriavidus necator, Pseudomonas oleovorans, and Escherichia
coli [80]. These microorganisms naturally accumulate PHAs, especially polyhydroxybu-
tyrate (PHB), as their principal lipid reserve within cellular membranes in the form of
granules under conditions of metabolic stress (Figure 4) [81].
Biopolymer biosynthesis occurs at the cytoplasmic level when there is an excess of
carbon and a deficiency of other vital nutrients required for cell proliferation, including
phosphorus, nitrogen, and magnesium. Under such circumstances, intracellular accumula-
tion of the biopolymer in granular form serves as a reservoir of carbon and energy [82].
This phenomenon mirrors the industrial emulsion polymerization process with re-
markable precision. It serves as a captivating and exemplary instance of how certain
biological processes can be seamlessly integrated into industries, catalyzing a new revolu-
tion centered around the effective harnessing of biological mechanisms. These mechanisms
are renowned for their energy efficiency, high selectivity, and environmental friendliness,
making them ideal candidates for integration into traditional industrial processes [83,84].
From a structural point of view, polyhydroxy alcanoates are composed of hydroxylated
fatty acid monomers that polymerize via ester bond formation with each monomeric unit
bearing the alkylic chain as a side chain (Figure 5).
 This phenomenon mirrors the industrial emulsion polymerization process with re
making
markable them ideal candidates
precision. It serves asfor integration into
a captivating and traditional
exemplary industrial
instance ofprocesses [83,84]
how certain bio
logical processes can be seamlessly integrated into industries, catalyzing a new revolutio
centered around the effective harnessing of biological mechanisms. These mechanisms ar
Polymers 2024, 16, 950 renowned for their energy efficiency, high selectivity, and environmental9 friendliness
of 23
making them ideal candidates for integration into traditional industrial processes [83,84]

Figure 4. Cupriavidus necator DSM 545, a metalophilic strain, containing PHA granules (bright in
tracellular inclusions) cultivated in continuous mode on glucose as the carbon source, imaged using
STEM, magnification ×30,000. Picture taken by E. Ingolić, FELMI-ZFE Graz, and provided by M
Koller, University of Graz, Austria [83].

Figure
Figure 4.4.Cupriavidus
From Cupriavidus
a structural necator
necator DSM
point DSM 545,
of545, a polyhydroxy
metalophilic
a metalophilic
view, strain,
strain, containing
containing
alcanoates are PHA
PHA granules
granules
composed of(bright
(bright hydroxin
tracellular inclusions) cultivated in continuous mode on glucose as the carbon source, imaged
intracellular inclusions) cultivated in continuous mode on glucose as the carbon source, imaged using usin
ylated fatty acid monomers that polymerize via ester bond formation with each mono
STEM,magnification
STEM, magnification ×30,000.
×30,000. Picture
Picture taken
taken by E.by E. Ingolić,
Ingolić, FELMI-ZFE
FELMI-ZFE Graz,
Graz, and and provided
provided by M. by M
meric unit bearing the alkylic chain as a side chain (Figure 5).
Koller,University
Koller, University of Graz,
of Graz, Austria
Austria [83].[83].

From a structural point of view, polyhydroxy alcanoates are composed of hydrox

ylated fatty acid monomers that polymerize via ester bond formation with each mono
meric unit bearing the alkylic chain as a side chain (Figure 5).

Figure5.5. (a)
Figure (a) General
Generalstructure
structureofofpolyhydroxy
polyhydroxy alkanoates
alkanoates (PHAs).
(PHAs). Each
Each monomer
monomer bears
bears a side chain
a side
(-R). Usually,
chain m can
(-R). Usually, range
m can from
range from1 1toto88 carbon atoms,while
carbon atoms, whilen nranges
ranges from
from 100 100 to 3000
to 3000 units.units. (b
Representation
(b) Representationofof some small-chain-length
some small-chain-length (SCL-HA)
(SCL-HA) and medium-chain-length
and medium-chain-length (MCL-HA)(MCL-HA)
side side
groups.Adapted
groups. Adapted from
from reference
reference [85].[85].

2.2.1.
FigureClassification
5. (a) Generalofstructure
Polyhydroxyoctanoate
of polyhydroxy alkanoates (PHAs). Each monomer bears a side chai
(-R).PHA
Usually, m canare
polymers range from 1 into
categorized to 8 three
carbon atoms,
groups while
based onntheir
ranges from and
structure 100 to 3000 units. (b
molecu-
Representation
lar of some
size: short chain lengthsmall-chain-length
(SCL-PHA), medium (SCL-HA) and medium-chain-length
chain length (MCL-PHA) and long(MCL-HA)
chain sid
length
groups.(LCL-HA) [84–86].
Adapted from In terms
reference [85].of chain length, SCL-PHAs are the most commonly
synthetized and studied [87].
Short-chain compounds consist of repeating 3 to 5 carbon building blocks (C3 -C5 ).
Some examples are poly (3-hydroxyvalerate) (PHV) and poly (3-hydroxybutyrate) (PHB),
which is one of the most investigated PHA polymers. Medium-chain polymers (MCL-PHA,
C6 -C14 ) contain between 6 and 14 carbon monomers. A good example of such PHA is poly(3-
hydroxyoctanoate) (PHO), which can be obtained from Pseudomonas mendocina. Lastly,
long-chain PHAs encompass longer monomeric units (number of carbon atoms ≥ 15). They
are the least common type of PHAs and are usually obtained from Shewanella oneidensis
and Aureispira marina [84–86,88–91].
The differentiation in chain length/monomeric unit is achieved by selecting appropri-
ate bacteria. Each microorganism has the ability to produce distinct types of monomeric
Polymers 2024, 16, 950 10 of 23

units. This variance in chain size primarily stems from the substrate specificity of PHA syn-
thases (PhaC): enzymes responsible for catalyzing hydroxy acids within a specific carbon
length range and integrating them into the growing polymer chain [79,92].
For instance, Cupriavidus necator is renowned for synthesizing PHA plastics when
provided with excess sugar substrate, with PHA accumulation levels reaching up to ap-
proximately 90% of the cell’s dry weight [93]. The PHA produced by this bacterium
typically consists of monomers with a small number of carbon atoms, such as poly(3-
hydroxyvalerate) (PHV) and poly(3-hydroxybutyrate) (PHB) [94]. On the other hand,
Pseudomonas mendocina produces PHA composed of medium-molecular-weight monomers,
imparting elastomeric properties and a relatively low mechanical strength [95]. In contrast,
Pseudomonas aeruginosa synthesizes PHA composed of high-molecular-weight monomers,
exemplified by poly(3-hydroxypentadecanoate).

2.2.2. Biosynthesis of Polyhydroxy Alcanoates

The biosynthesis of PHAs is strictly linked to different kind of metabolic pathways.
Among them, the most notorious is the one involved in the synthesis of PHB [96]. The
method used to produce PHB involves starting from carbon sources such as glucose,
sucrose, or lactose that are converted through different enzymatic reactions to acetyl-CoA.
Under metabolic stress, acetyl-CoA enters the metabolic pathway of ketone bodies and is
converted into PHB in three steps: 3-ketothiolase transform acetyl-CoA into acetoacetyl-
CoA, which is then converted into (R)-3-hydroxybutyryl-CoA via the action of acetoacetyl-
CoA reductase via a NADH-dependent mechanism of action. Finally, PHB synthase
catalyze the polymer formation [81,97,98].

2.2.3. Chemical and Physical Properties of Polyhydroxy Alcanoates

The monomeric composition of microbial PHAs is influenced by many factors, such
as the strain of bacteria used, the composition of the growth medium, the carbon source,
and the overall cultivation conditions. Consequently, PHA polymers can display a wide
range of chemical, thermal, and mechanical properties, varying from rigid and brittle with
a high crystallinity percentage to elastomeric polymers, thereby enabling diverse industrial
applications. It is worth remembering that the properties of the polymeric material are
closely related to the structure of the monomer (e.g., length of the side chain, length of the
monomeric backbone, etc.). Therefore, the properties of PHA can be modified physically,
chemically, or biologically to tune them to different applications [86,99,100].
Despite their potential for commercial use, many PHA-based materials still present
some challenges that researchers need to tackle. For instance, poly(3-hydroxybutyrate)
(PHB), one of the most-studied and characterized PHA-based polymers, is highly hy-
drophobic and exhibits low heat distortion temperatures and poor gas barrier properties.
PHB, with its high crystallinity percentage (up to 80%), suffers from poor mechanical prop-
erties, making it unsuitable for various applications including packaging, biomedical and
pharmaceutical uses like heart valves, vascular applications, and controlled drug delivery
systems [101]. Additionally, PHA production costs are higher compared to other bio-based
plastics, limiting their applications due to their undesirable physical properties.
Various approaches have been devised to enhance the physical and chemical prop-
erties of PHAs, aiming to overcome these limitations by modifying the biopolymers
physically, chemically, or biologically to broaden their applications across different fields
(Figure 6) [102,103]. There are several methods to tune and improve PHA properties, the
most important of which are physical modification via blending with other polymeric
materials and chemical modification of the polymeric chain.
 Various approaches have been devised to enhance the physical and chemical proper-
ties of PHAs, aiming to overcome these limitations by modifying the biopolymers physi-
cally, chemically, or biologically to broaden their applications across different fields (Fig-
ure 6) [102,103]. There are several methods to tune and improve PHA properties, the most
Polymers 2024, 16, 950 11 of 23
important of which are physical modification via blending with other polymeric materials
and chemical modification of the polymeric chain.

Figure 6.
Figure 6. Graphical
Graphical representation
representationof
ofthe
thepossible
possibleways
waysto
toachieve
achievePHA
PHAmodification
modification[84,104].
[84,104].

Blending
Blending
With
With regard
regardtotophysical
physicalmodification,
modification, blending
blending PHA
PHA with
with natural
natural raw
raw materials
materials and
and
with
with synthetic biodegradable polymers is a highly studied technique in the literature.
synthetic biodegradable polymers is a highly studied technique in the literature. A
A
polymer
polymerblend
blendhas
hasbeen
beendefined
definedbybyIUPAC
IUPACasas “a“a
macroscopically homogeneous
macroscopically homogeneous mixture of
mixture
two or or
of two more
moredifferent
differentpolymers”
polymers” [105]. InInpolymer
[105]. polymertechnology,
technology,blending
blendingisisaacaptivating
captivating
solution that, by mixing a defined polymeric matrix with other substances, can allow
solution that, by mixing a defined polymeric matrix with other substances, can allow re-
researchers to obtain new polymeric materials with improved properties.
searchers to obtain new polymeric materials with improved properties.
One of the major advantages of this approach to polymer modification relies in the
One of the major advantages of this approach to polymer modification relies in the
possibility of tuning the properties of the original polymer to make it compatible with
possibility of tuning the properties of the original polymer to make it compatible with a
a specific and desired application [106]. Researchers have explored numerous low-cost,
specific and desired application [106]. Researchers have explored numerous low-cost,
high-value raw materials and bio-based polymers as additives to modify PHA properties
high-value raw materials and bio-based polymers as additives to modify PHA properties
and create materials with enhanced characteristics. Some of the most notable examples
and create materials with enhanced characteristics. Some of the most notable examples
include blending with natural polymers such as cellulose, starch, and lignin.
include blending with natural polymers such as cellulose, starch, and lignin.
• Cellulose derivatives have garnered significant attention as viable blending agents
• Cellulose derivatives have garnered significant attention as viable blending agents
with PHA due to their compatibility and capacity to accelerate PHA degradation rates.
with PHA due to their compatibility and capacity to accelerate PHA degradation
The incorporation of cellulose derivatives like cellulose acetate butyrate (CAB) has
rates. The incorporation of cellulose derivatives like cellulose acetate butyrate (CAB)
demonstrated notable enhancements in the various physical and mechanical properties
has demonstrated notable enhancements in the various physical and mechanical
of PHA, including but not limited to a PHB concentration-dependent increase in the
properties of PHA, including but not limited to a PHB concentration-dependent
Tg and an increase in the elongation at break of up to 7%. The utilization of PHA
blends with cellulose derivatives has found diverse applications in the pharmaceutical
and medical domains. These blends serve as effective carriers for poorly soluble drugs,
facilitate blood coagulation processes, and are employed in pharmaceutical tablet
coating, among other uses [107–109].
• Starch, being among the most promising natural polymers, boasts inherent biodegrad-
ability and widespread availability. Poly-3-hydroxybutyrate (PHB) stands out as the
predominant type of PHA utilized thus far in formulating blends with starch [110].
The blending of PHA with starch or its derivatives has shown promise in reduc-
ing production costs while enhancing mechanical properties. Notably, studies have
demonstrated the viability of blending thermoplastic starch with PHB. Incorporating
thermoplastic starch at levels of up to 30 wt% with PHB has yielded improvements in
tensile strength, Young’s modulus, and elongation at break when compared to pure
Polymers 2024, 16, 950 12 of 23

PHB, all while yielding a more cost-effective material. These blends have expanded
the potential applications of PHB as a coating material for food packaging, particularly
on paper or cardboard substrates. Despite these benefits, blending PHAs with starch
still presents challenges to tackle due to their inherent incompatibility, leading, for
example, to difficulties in the production of non-brittle films [110–112].
• Lignin is a natural amorphous biopolymer made of repeating units of phenylpropane,
featuring both aliphatic and aromatic hydroxyl groups, along with carboxylic acid
groups [113]. The presence of these functional groups makes lignin a valuable ma-
terial for blending purposes with PHA. It was demonstrated that lignin has a good
miscibility with PHB, and lignin’s amorphous structure can decrease the formation of
large spherulite crystals and secondary nucleation, which significantly affects the brit-
tleness of PHB [114]. The studies of Kai et al. have shown that lignin and its butyrate
derivative exhibit a high miscibility with PHB, and that it can affect PHB crystalliza-
tion. In particular, it was demonstrated that lignin can effectively slow down PHB
crystallization. These findings suggest that lignin fine powder could serve as a novel
type of nucleating agent to modulate PHB crystallization [115]. The thermo-physical
properties and rheology of PHB/lignin blends were deeply studied by Mousavioun
et al. Their findings, based on TGA, DSC, and SEM analyses of the PHB/soda lignin
blends, suggest that intermolecular interactions between PHB and soda lignin are
favored at a soda lignin content of up to 40 wt%. These interactions are attributed to
the formation of hydrogen bonds between the reactive functional groups of lignin and
the carbonyl groups of PHB. While soda lignin enhances the overall thermal stability
of PHB, it also reduces the initial decomposition temperature of PHB [116].

Chemical Modification
Chemical modification represents another promising solution for enhancing PHAs’
properties by introducing additional chemical groups into the PHA structure. Polyhy-
droxyalkanoates (PHAs) can undergo modifications through the incorporation of various
chemical groups, leading to the development of chemically modified PHAs with enhanced
functionalities. These modified PHAs hold potential for utilization as multifunctional
materials. The most common chemical modifications involve carboxylation, halogenation,
hydroxylation, epoxidation, and grafting processes on the PHA polymeric matrix.
The carboxylation process consists of the creation of -COOH functional groups, of-
ten mediated by KMnO4 as an oxidation agent [117]. This type of modification was
demonstrated to be efficient in enhancing the hydrophilicity of the polymer [118]. The
halogenation of PHA stands out as a remarkable method for enhancing the properties,
functionalities, and applications of polymers.
The introduction of halogen atoms (such as chlorine, bromine, and fluorine) can be per-
formed on both unsaturated and saturated PHA through addition or substitution reactions
depending on the chemical characteristics of the substrate. This method offers a versatile
means of broadening the functionalities and applications of the polymer. Depending on
the quantity of halogen introduced, the resulting PHA demonstrates elevated melting and
glass transition temperatures. However, this method also presents the drawback of reduced
biocompatibility [119].
Hydroxylation presents a method to achieve a reduction in the molecular weight of the
original polymer chain via hydrolysis reactions. This can proceed either through an acid- or
base-catalyzed reaction and is usually carried out in the presence of low-molecular-weight
mono or diol compounds. The most common methods employ either sodium hydroxide or
para-toluene sulfonic acid (PTSA). PHA modified by these reactions might exhibit lower
glass transition and melting temperatures [120].
Epoxidation represents a chemical modification method with the potential to enhance
the thermal stability of PHA. This process involves converting double carbon–carbon bonds
into epoxy groups. The high reactivity and facile conversion of epoxy groups into anionic
Polymers 2024, 16, 950 13 of 23

and polar groups, even under mild conditions, underscore the significance of epoxidation
as a pivotal strategy for PHA modification [121].
Grafting emerges as a highly reliable chemical modification method for PHA, wherein
monomers are covalently bonded or “grafted” onto the polymer chain to achieve de-
sired properties. This approach holds promise in preserving the inherent characteristics
of PHA while introducing new ones. Various grafting methods are available, including
radiation-based, enzyme-based, ionic, or radical grafting. Generally, this type of modifica-
tion ensures minimal loss of original properties while imparting additional properties to
the polymer [122,123].

2.2.4. Applications of Polyhydroxyalcanoates

In terms of applications, PHAs can be employed across various fields, such as medicine,
agriculture, and packaging, owing to their biodegradability, biocompatibility, and non-
toxic nature.
PHA materials are extensively utilized in the medical industry owing to their excellent
biodegradability and biocompatibility. PHA particles exhibit non-toxicity and are devoid of
any pyrogenic, allergenic, carcinogenic, inflammatory, or teratogenic properties [124]. The
employment of PHA beads has proven to be useful for medical and industrial applications
such as protein purification [125], diagnostics and imaging [126,127], tissue engineering, etc.
In the medical field, PHA serves as a valuable material for drug delivery systems
including nanoparticles and encapsulation of active pharmaceutical ingredients [128,129].
The in vivo and in vitro cytotoxicity of PHA carriers have been studied. A recent paper by
Pevic et al. proved how the use MCL-PHA as a drug delivery system can both improve
therapeutic effects and reduce systemic drug toxicity [130]. Bokrova et al. developed novel
combined PHB–liposome nanoparticles and assessed their cytotoxicity in mammalian cells
in vitro. The newly combined PHB–liposome particles demonstrated no toxicity to HEK
(human embryonic kidney) and HaCaT (human immortalized keratinocyte) cells [131].
These PHB nanoparticles (NPs) exhibit potential as active carriers for both hydrophobic and
hydrophilic active ingredients, including antioxidants, anti-aging compounds, complex nat-
ural extracts, and antibacterial agents [124]. PHA particles offer versatility in modifications
through various surface-binding proteins, thereby expanding their practical applications
and reducing PHA nanoparticle cytotoxicity [132]. In a study by Fan et al., the natural
PHA binding protein PhaP was effectively adsorbed onto PHB NPs through hydrophobic
interactions and used as a drug delivery system for targeted accumulation in prostate
tumors. This system allowed for a remarkably enhanced cellular uptake in the human
prostate cancer cell line PC3 compared to non-functionalized NPs. This study demonstrates
the potential of surface-modified PHA nanoparticles to enhance or target phagocytosis,
thus paving the way for their potential clinical application in the future [133].
Spherical polyhydroxyalkanoates have also found many applications in the vaccine
engineering field [134]. Given that PHB has received approval from the U.S. Food and Drug
Administration (FDA) for clinical studies, and that its 3-hydroxybutyric acid component is
a natural constituent of human blood, this type of PHA has been proposed as a safe option
for use as an antigen carrier in vaccine formulations [135,136].
PHAs have been studied and used to produce PHA bead-based particles embodied
with specific antigens as vaccines formulations against different biological agents such
as Pseudomonas aeruginosa [137], Mycobacterium tuberculosis [138–141], Streptococcus pneu-
moniae [142–144], and Neisseria meningitidis [145]. Additionally, PHA is utilized in tissue
engineering to fabricate scaffolds for regenerative medicine purposes [146–148]. PHA is
also employed in the agricultural field, not only as an encapsulating agent for pesticides and
to control their release kinetics but also as a seed-protecting agent [149]. The packaging and
food service industries utilize PHA due to its biodegradability and permeability properties,
making it an attractive alternative to petroleum-based plastics. PHA-based packaging films
are utilized in the production of plastic bags, cups, and similar products [150].
 ployed in the agricultural field, not only as an encapsulating agent for pesticides and to
control their release kinetics but also as a seed-protecting agent [149]. The packaging and
food service industries utilize PHA due to its biodegradability and permeability properties,
making it an attractive alternative to petroleum-based plastics. PHA-based packaging films
Polymers 2024, 16, 950 14 of 23
are utilized in the production of plastic bags, cups, and similar products [150].

2.3. Polyhydroxy Polyamides

2.3. Polyhydroxy Polyamides
A polyamide, by definition, is a condensation product in which the monomers are
A polyamide,
linked via an amideby definition,
bond. Perhapsisthe
a condensation
most renowned product in which
polyamide the monomers
is Nylon-6,6, are
which has
linked via an amide bond. Perhaps the most renowned polyamide is Nylon-6,6,
led to polyamides being commonly referred to as “nylons” in a general sense. Linear pol- which
has led toare
yamides polyamides being commonly
formed through referred
a condensation to as “nylons”
reaction betweeninbifunctional
a general sense. Linear
monomers.
polyamides are formed through a condensation reaction between bifunctional monomers.
When amino acids or their lactam forms are used as monomers, the resulting polymer is
When amino acids or their lactam forms are used as monomers, the resulting polymer is
classified as an AB type polymer, with A representing the amino group and B the carbox-
classified as an AB type polymer, with A representing the amino group and B the carboxylic
ylic group. The resulting polyamide is denoted as nylon-n, with n representing the num-
group. The resulting polyamide is denoted as nylon-n, with n representing the number
ber of carbon atoms between the amino and carboxylic termini. Similarly, polymers re-
of carbon atoms between the amino and carboxylic termini. Similarly, polymers resulting
sulting from the reaction between a diamine and a dicarboxylic acid are classified as AABB
from the reaction between a diamine and a dicarboxylic acid are classified as AABB type,
type, with two numbers (m, n) indicating the number of carbon atoms separating the
with two numbers (m, n) indicating the number of carbon atoms separating the amino and
amino and carboxylic functional groups, respectively (Scheme 2) [151].
carboxylic functional groups, respectively (Scheme 2) [151].

Scheme 2. Polyamide
Scheme 2. Polyamide types.
types.

The physical properties of nylons are closely tied to the distance between the func-
The physical properties of nylons are closely tied to the distance between the func-
tional groups and thus the length of the polyethylene chain. Consequently, common
tional groups and thus the length of the polyethylene chain. Consequently, common ny-
nylons exhibit very similar performances, displaying a “monotonous behavior”, in con-
lons exhibit very similar performances, displaying a “monotonous behavior,” in contrast
trast to natural polymers, which exhibit greater diversity in their physical, chemical, and
to natural polymers, which exhibit greater diversity in their physical, chemical, and bio-
biological functions [152]. This has led to the gradual replacement of these polymers
logical functions [152]. This has led to the gradual replacement of these polymers with
with high-performance materials ad hoc designed to express improved biocompatibility,
high-performanceand
biodegradability, materials ad hocproperties
other desired designed to express improved biocompatibility, bio-
[153].
degradability, and other desired properties [153].
Efforts have already been made to synthesize biodegradable nylons, with findings
Efforts
indicating have
that already been
polyamides mademethyl
containing to synthesize biodegradable
and hydroxyl nylons, with
groups demonstrate findings
biodegrad-
indicating
ability. that polyamides
Furthermore, containing
the presence methyl and hydroxyl
of electron-withdrawing groups demonstrate
substituents biodeg-
near the carbonyl
radability. Furthermore, the presence of electron-withdrawing substituents near
groups has been shown to enhance their hydrolysis rate [154]. Biodegradable synthetic the car-
bonyl groups has been shown to enhance their hydrolysis rate [154]. Biodegradable
polymers are typically designed to mimic natural peptides or proteins to enhance both
chemical and enzymatic hydrolysis of the final product. From a synthetic perspective,
introducing asymmetric carbons into the polyamide backbone allows for control over the
physical properties of the polymer by modulating the tacticity of the macromolecule [155].
Carbohydrate-based synthetic polymers can be prepared through the polymerization
reaction of appropriate activated monomers. Overall, the interest in polyaldaramides has
increased in the past decade. Polyaldaramides, also known as polyhydroxypolyamides
(PHPAs) or hydroxylated nylons, are hydroxylated, linear polyamides of the AABB type,
where the diacid monomer units of typical nylons are replaced by an aldaric acid. Al-
daric acids are dicarboxylic acids derived from the oxidation of aldoses. Their chemical
nature and renewable origin make them promising candidates as monomers or build-
ing blocks for the synthesis of biobased polymers, particularly hydroxylated polyesters
and polyamides [156,157]. In terms of environmental impact, these compounds have gar-
nered significant attention due to the renewable nature of the carbohydrate backbone of
 where the diacid monomer units of typical nylons are replaced by an aldaric acid. Aldaric
acids are dicarboxylic acids derived from the oxidation of aldoses. Their chemical nature
and renewable origin make them promising candidates as monomers or building blocks
for the synthesis of biobased polymers, particularly hydroxylated polyesters and polyam-
Polymers 2024, 16, 950 ides [156,157]. In terms of environmental impact, these compounds have garnered signif- 15 of 23
icant attention due to the renewable nature of the carbohydrate backbone of the monomer
unit and their high degradability in soil, especially when compared with traditional ny-
lons or poly(ethylene
the monomer unit and terephthalate) [158,159].
their high degradability in soil, especially when compared with
The regio-
traditional nylonsandorstereochemical
poly(ethylene properties
terephthalate) of the macromolecule depend on the con-
[158,159].
figuration of theand
The regio- chosen monomers. properties
stereochemical Although derivatives of aldaric acids
of the macromolecule depend couldon have been
the config-
employed
uration of in thepolymerization
chosen monomers. reactions,
Althoughtheir derivatives
applicationofinaldaric
this regard
acids wascouldnot investi-
have been
gated until in
employed thepolymerization
1950s. In fact, the first example
reactions, of these polymers
their application was reported
in this regard was notby Wolform
investigated
et al. in
until the1958 [159],
1950s. In and
fact, later on, example
the first more in-depth
of thesestudies of these
polymers waspolymers
reported were carried et
by Wolform outal.
in Ogata
by 1958 [159],
et al.and later on,
in Japan more
in the in-depth
1970s. studies of work
The pioneering these polymers
by Ogata et were carried out by
al. demonstrated
Ogata
that theetcondensation
al. in Japan in the 1970s.
between The pioneering
a diethyl ester of anwork by acid
aldaric Ogata et al.asdemonstrated
(such that
tartaric or galac-
the condensation
taric) and a diamine between a diethylunder
could proceed ester mild
of anconditions.
aldaric acidIt(such as tartaric
was found or galactaric)
that the presence
and
of a diamine could
heteroatomic groupsproceed
(such asunder
ether mild conditions.
or hydroxyl It wasgroups)
functional found thatin thetheα-presence
or β-posi- of
heteroatomic
tion to the estergroups
group(such
greatlyas enhanced
ether or hydroxyl functional
the reactivity of thegroups) in the α- or
diester monomer inβ-position
polymer-
to the ester
ization group
reactions greatly
carried enhanced
out the reactivity
in polar solvents of the diester
[158,160,161]. monomer in polymeriza-
The polymerization of diethyl
tion reactions carried out in polar solvents [158,160,161]. The
galactarate with hexamethylenediamine yielded a hydroxylated analogue of nylon-6,6 polymerization of diethyl
galactarate
that did not with
melt hexamethylenediamine
or decompose at 200 °C.yielded a hydroxylated
These reactions analogue in
were performed of solvents
nylon-6,6such
that
did not melt dimethyl
or decompose ◦ C. These reactions were performed in solvents such
at 200and
as methanol, sulfoxide, N-methylpyrrolidone under mild conditions. The
as methanol,
increased dimethyl
reactivity sulfoxide,
of esters toward and N-methylpyrrolidone
aminolysis underofmild
due to the presence conditions.
the hydroxyl The
group
increased reactivity of esters toward aminolysis due to the presence
was attributed to hydrogen bonding of the -OH group with the approaching amino group of the hydroxyl group
was
in theattributed
intermediateto hydrogen
reaction bonding of the 3).
stage (Scheme -OH group with the approaching amino group
in the intermediate reaction stage (Scheme 3).

Scheme
Scheme3.3.Hydrogen
Hydrogenbond
bondstabilization
stabilizationof
ofthe
theintermediate
intermediatereaction
reaction stage.
stage.

Furtherexamination
Further examinationof ofthis
thisreaction
reactionwas
wascarried
carriedout
outby
byHoagland
Hoaglandetetal.,
al.,who
whoinvesti-
investi-
gatedthe
gated thereaction
reactionmechanisms
mechanismsof ofaminolysis
aminolysisofofsix-carbon
six-carbongalactaric
galactaricacid
aciddiesters
diesters[162].
[162].
They found
Polymers 2024, 16, x FOR PEER REVIEW
They foundthat
thatthe
theaminolysis
aminolysis proceeds
proceeds through
through a two-step
a two-step sequence:
sequence: a fast,a base-cata-
fast,
16 base-
of 25
catalyzed
lyzed lactonization
lactonization to give
to give the γ-lactone
the γ-lactone intermediate,
intermediate, followed
followed by the
by the slowslow aminolysis
aminolysis of
of the lactone (Scheme
the lactone (Scheme 4). 4).

Scheme 4. General aminolysis pathway demonstrated by Hoagland et al. [162].

Scheme 4. General aminolysis pathway demonstrated by Hoagland et al. [162].
The lactonization of the ester appears to be much faster than the aminolysis of the ester.
The lactonization of the ester appears to be much faster than the aminolysis of the ester.
This study by Hoagland et al. demonstrates that the activation of the aldaric acid diesters
This study
is due byeasy
to the Hoagland et al.ofdemonstrates
formation that thefive-membered
the highly reactive activation of thealdarolactones
aldaric acid diesters
[162]. is
due to the easy formation of the highly reactive five-membered aldarolactones [162].
Polyaldaramides are typically prepared using aldaric acid monomers that are acti-
vated as esters or acyl chlorides, often with acetylated protected hydroxyl groups. Poly-
amides with free hydroxyl groups are then obtained via deacylation in aqueous ammonia.
The synthesis of unprotected activated D-glucaric acid dimethyl or diethyl ester mono-
mers and their polymerization were first investigated and patented by Kiely et al.
Polymers 2024, 16, 950 16 of 23

Polyaldaramides are typically prepared using aldaric acid monomers that are activated
as esters or acyl chlorides, often with acetylated protected hydroxyl groups. Polyamides
with free hydroxyl groups are then obtained via deacylation in aqueous ammonia. The
synthesis of unprotected activated D-glucaric acid dimethyl or diethyl ester monomers
and their polymerization were first investigated and patented by Kiely et al. [163,164].
The initial polyhydroxypolyamide (PHPA) reported by Kiely was prepared under Fisher
esterification conditions in methanol. Subsequent reports on the synthesis of D-glucaric
acid-based PHPAs have focused on the use of methyl D-glucaro-1,4 lactone as the starting
monomer [165]. Carbohydrate-derived polyamides exhibit interesting properties, partic-
ularly in terms of crystallinity, which is typically associated with chain stereoregularity.
AABB-type polyamides obtained through conventional polycondensation are stereoregular
when their monomers have a 2-fold axis of symmetry. Otherwise, they may enter the poly-
mer chain in two opposite orientations, giving rise to non-stereoregular polyamides. The
polyglucaramides obtained using the above-mentioned protocol are termed stereo-random
because D-glucaric acid does not have a symmetrical structure and therefore gives rise to
randomly oriented glucaric acid units in the backbone of the macromolecule [166]. In fact,
such symmetry restriction is met only by the aldaric- or alditol-based monomers having
threo-, manno-, and ido-configuration. Nonetheless, stereoregular AABB-type polyamides
derived from non-centrosymmetric D-glucaric acid have been prepared by Kiely et al. using
synthetic methods that can differentiate between the reactivity toward the aliphatic diamine
of the aldaric acid’s two carboxyl groups [157].
While efforts have been focused on understanding the chemical behavior and finding
convenient
Polymers 2024, 16, x FOR PEER REVIEW synthesis pathways for PHPAs derived from D-glucaric acid, meso-xylaric acid,
17 of 25
and L-mannaric acid, little investment has been made in using galactaric acid derivatives
as starting monomers (Scheme 5).
OH
R’-OH COOR’ O H 2N NH2 OH OH O
O R
(a) Glucaric acid R
N N
- H2 O -R’OH H H n
HO OH O OH OH

OH OH H2N NH2 OH OH O
R’-OH R
COOR’ R
(b) Glucaric acid COOR’ N N
- H2O -R’OH H H n
OH OH O OH OH

R’ = Me- or Et-

OH OH OH O OH OH O
H2N NH 2 Δ
COOR’ O O R R R
-OOC NH + N N
(c) Galactaric acid NH3
H H n
- H2 O OH OH - H2O O OH OH
HO OH
Zwitterionic monomer

Telescoped reaction

Scheme
Scheme 5.5. Synthetic
Synthetic procedure
procedure for
for the
the synthesis
synthesis of
of polyhydroxy
polyhydroxy polyamides,
polyamides, modified
modifiedfrom
fromrefer-
refer-
ence [167], (a) synthetic path involving protection and lactone formation first, (b) polycondensation
ence [167], (a) synthetic path involving protection and lactone formation first, (b) polycondensation
using diester monomers and (c) more recent polymerization technique using zwitterionic mono-
using diester monomers and (c) more recent polymerization technique using zwitterionic monomers.
mers.
Only a few examples of poly(galactaramides) being synthesized and partially charac-
Only
terized areapresent
few examples of poly(galactaramides)
in the literature. Usually, the mostbeing synthesized
convenient methodandreported
partiallyforchar-
the
acterized
synthesis of polyhydroxy polyamides from galactaric acid is using galactaric acid estersfor
are present in the literature. Usually, the most convenient method reported as
the synthesis
starting of polyhydroxy
monomers (Scheme 5b) polyamides
[168–170].from
Withgalactaric
the aim ofacid is using
avoiding thegalactaric acid es-
use of protective
ters as starting
groups monomers
and favoring (Scheme
a rigorous 5b) [168–170]. With
1:1 diacid-diamine ratiothe aim of
control, avoiding the
Gambarotti usereported
et al. of pro-
tective groups and favoring a rigorous 1:1 diacid-diamine ratio control, Gambarotti
the synthesis of a new zwitterionic monoamide of galactaric acid to be used as a building et al.
reported the synthesis of a new zwitterionic monoamide of galactaric acid
block in the polymerization reaction (Scheme 5c). This protocol involved the conversion to be used as a
building block in the polymerization reaction (Scheme 5c). This protocol involved
of galactaric acid into the corresponding γ-galactaro lactone first, followed by its reaction the con-
version of galactaric
with diamines acid
leading tointo the corresponding
the formation γ-galactaro lactone
of the corresponding first, followed
zwitterionic by its
monoamides
reaction
with good with diamines
yields leading to the
and selectivity. formation
This new classof the corresponding
of monomers was zwitterionic
then employed mono- in
amides with good yields and selectivity. This new class of monomers was then employed
in polymerization to obtain the corresponding poly(galactaramides), showing a high atom
economy and comparable degree of polymerization (DP) usually obtained by using the
protected galactaric ester form [167].
In terms of application, polyaldaramides, which appear to be biocompatible and bi-
Polymers 2024, 16, 950 17 of 23

polymerization to obtain the corresponding poly(galactaramides), showing a high atom

economy and comparable degree of polymerization (DP) usually obtained by using the
protected galactaric ester form [167].
In terms of application, polyaldaramides, which appear to be biocompatible and
biodegradable, offer easy access to a wide range of polymers that can be applied as
biodegradable adhesives, timed release fertilizers, industrial chemicals for the textile and
paper industries, water treatment chemicals, detergent components, hydrogel components,
and film and fiber materials [171]. Also, an interesting study was published demonstrating
that poly(glucaramides) can form a nanoparticulate system that can be used for slow and
controlled release applications [172].

3. Conclusions
In conclusion, the exploration of bio-based polymers such as PLA, PHA, and poly-
hydroxy polyamides unveils a promising frontier in sustainable material science. These
polymers offer a compelling alternative to traditional petroleum-based plastics, exhibiting
comparable or even superior properties while significantly reducing environmental impacts.
Their versatility and compatibility with various applications ranging from packaging to
biomedical devices underscore their potential to revolutionize the polymeric material sector
and industry. While challenges such as cost-effectiveness, scalability, and processability
remain, ongoing research and technological advancements continue to drive innovation
in this field. As we move towards a more sustainable future, the adoption of bio-based
polymers stands as a crucial step in mitigating plastic pollution and fostering a greener,
more resilient global economy. Through collaborative efforts between academia, industry,
and policymakers, the integration of these eco-friendly materials into mainstream usage
holds the promise of a brighter, more sustainable tomorrow.

Author Contributions: Conceptualization, G.I.C.R. and A.F.; methodology, G.I.C.R., F.F. and A.F.; val-
idation, G.I.C.R. and F.F.; formal analysis, G.I.C.R. and F.F.; investigation, G.I.C.R. and F.F.; resources,
G.I.C.R., F.F. and A.F.; data curation, G.I.C.R. and F.F.; writing—original draft preparation, G.I.C.R.
and F.F.; writing—review and editing, G.I.C.R., F.F. and A.F.; visualization, G.I.C.R., F.F. and A.F.;
supervision, G.I.C.R. and A.F.; project administration, G.I.C.R. and A.F.; funding acquisition, A.F. All
authors have read and agreed to the published version of the manuscript.
Funding: This research did not receive any external funding.
Institutional Review Board Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors warmly thank Lee for their assistance.
Conflicts of Interest: The authors declare no conflicts of interest.

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