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3D and 4D Printing in the Fight against Breast Cancer

Authors:
  • Università degli Studi di Urbino Carlo Bo
Article

3D and 4D Printing in the Fight against Breast Cancer

Abstract and Figures

Breast cancer is the second most common cancer worldwide, characterized by a high incidence and mortality rate. Despite the advances achieved in cancer management, improvements in the quality of life of breast cancer survivors are urgent. Moreover, view the heterogeneity that char-acterizes tumors and patients, focusing on individuality is fundamental. In this context, 3D printing (3DP) and 4D printing (4DP) techniques allow for a patient-center approach. At present, 3DP applications against breast cancer are focused on three main aspects: treatment, tissue re-generation, and recovery of the physical appearance. Scaffolds, drug-loaded implants, and prosthetics have been successfully manufactured; however, some challenges must be overcome to shift to clinical practice. The introduction of the fourth dimension has led to an increase in the degree of complexity and customization possibilities. However, 4DP is still in the early stages, thus research is needed to prove its feasibility in healthcare applications. This review article provides an overview of current approaches for breast cancer management, including standard treatments and breast reconstruction strategies. The benefits and limitations of 3DP and 4DP technologies are discussed, as well as their application in the fight against breast cancer. Future perspectives and challenges are outlined to encourage and promote AM technologies in re-al-world practice.
Content may be subject to copyright.
Citation: Moroni, S.; Casettari, L.;
Lamprou, D.A. 3D and 4D Printing in
the Fight against Breast Cancer.
Biosensors 2022,12, 568. https://
doi.org/10.3390/bios12080568
Received: 28 June 2022
Accepted: 25 July 2022
Published: 26 July 2022
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biosensors
Review
3D and 4D Printing in the Fight against Breast Cancer
Sofia Moroni 1,2 , Luca Casettari 2and Dimitrios A. Lamprou 1, *
1School of Pharmacy, Queen’s University Belfast, Belfast BT9 7BL, UK; sofia.moroni@qub.ac.uk
2Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy;
luca.casettari@uniurb.it
*Correspondence: d.lamprou@qub.ac.uk
Abstract:
Breast cancer is the second most common cancer worldwide, characterized by a high
incidence and mortality rate. Despite the advances achieved in cancer management, improvements
in the quality of life of breast cancer survivors are urgent. Moreover, considering the heterogeneity
that characterizes tumors and patients, focusing on individuality is fundamental. In this context, 3D
printing (3DP) and 4D printing (4DP) techniques allow for a patient-centered approach. At present,
3DP applications against breast cancer are focused on three main aspects: treatment, tissue regen-
eration, and recovery of the physical appearance. Scaffolds, drug-loaded implants, and prosthetics
have been successfully manufactured; however, some challenges must be overcome to shift to clinical
practice. The introduction of the fourth dimension has led to an increase in the degree of complexity
and customization possibilities. However, 4DP is still in the early stages; thus, research is needed to
prove its feasibility in healthcare applications. This review article provides an overview of current
approaches for breast cancer management, including standard treatments and breast reconstruction
strategies. The benefits and limitations of 3DP and 4DP technologies are discussed, as well as their
application in the fight against breast cancer. Future perspectives and challenges are outlined to
encourage and promote AM technologies in real-world practice.
Keywords: 3D printing; 4D printing; additive manufacturing; drug delivery; breast cancer
1. Introduction
Breast cancer is the second most common cancer worldwide, especially among the fe-
male population. Male breast cancer is rare, involving only 0.5–1% of new cases [
1
]. Despite
the preventive strategies, such as screening mammography, visualization, and touching
the breast, cancer is often diagnosed late, resulting in high mortality. Indeed, according to
the World Health Organization (WHO), in 2020 it was estimated that
2.3 million
women
were diagnosed and around 30% of the cases died [
2
,
3
]. Breast cancer is a heterogeneous
disease; indeed, the etiology can be considered multifactorial, including both hereditary
and acquired factors. The heterogeneity involves patients and tumors, leading to a differ-
ence in the prognosis and treatments [
4
]. The primary risk factors are sex (female) and
age (over 40), but also family and medical history and an unhealthy lifestyle (e.g., weight,
unbalanced diet, alcohol consumption, smoking), which can increase the incidence [5,6].
Breast cancer is mostly derived from abnormalities in the epithelium (carcinoma),
and it encompasses a group of injuries that differ in microscopic aspects and biological
behavior. The natural evolvement of breast cancer consists of the progression from non-
invasive forms (in situ), in which tumor cells are limited to ducts or lobules, to invasive
forms characterized by the spread to the breast stroma and, lastly, to metastatic carcinomas
when the tumor spreads to distant sites. Non-invasive carcinoma can be ductal in situ or
lobular in situ. Ductal carcinoma in situ (DCIS) is the most common form of non-invasive
carcinoma, often associated with recidivism and progression to the invasive form known
as invasive ductal carcinoma. Invasive ductal carcinoma, also known as infiltrating ductal
Biosensors 2022,12, 568. https://doi.org/10.3390/bios12080568 https://www.mdpi.com/journal/biosensors
Biosensors 2022,12, 568 2 of 20
carcinoma, is the most common type of breast cancer [79]. A schematic representation of
breast cancer progression is reported in Figure 1.
Biosensors 2022, 12, x FOR PEER REVIEW 2 of 22
infiltrating ductal carcinoma, is the most common type of breast cancer [79]. A schematic
representation of breast cancer progression is reported in Figure 1.
Figure 1. Schematic illustration of breast cancer progression.
The growth and development of the mammary gland are dependent on complex in-
teractions between hormones (estrogen and progesterone) and growth factors (human ep-
idermal HER2) with their specific cellular receptors [10]. Estrogen stimulates the normal
growth of ducts, while progesterone is responsible for the development of the lobule and
alveolar. These lipophilic molecules easily diffuse through the membrane and bind to the
receptors present in the cytoplasm that are transported to the nuclei where they interact
with the DNA. This interaction will stimulate the genetic response that affects the normal
growth of the cell and its function. Thus, knowing the expression of hormones of the tu-
mor is important, as it allows for predicting the prognosis and the possible response to
the endocrine treatment and selecting the adequate therapy [6,11].
Conventionally, breast cancer can be classified according to the presence or absence
of three biomarkers: estrogen receptor (ER), progesterone receptor (PR), and human epi-
dermal growth factor receptor 2 (HER2), being called hormone receptor-positive or nega-
tive. However, the expression of ER, PR, and HER2 receptors is not universal; around 15
20% of breast cancers are hormone receptor-negative, called triple-negative breast cancers
(TNBCs). TNBC is an invasive cancer subtype, characterized by aggressive behavior, early
relapse, and metastases; in addition, TNBC does not respond to conventional treatments,
limiting the survival of patients [12,13].
Breast cancer not only concerns the potential survival of patients but also their well-
being, from the aesthetic and emotional point of view. During the last decade, efforts have
been made to improve the quality of life of patients and survivors by making progress in
the prevention, diagnosis, and treatment of this burden of disease.
This review article encompasses an overview of current strategies in the management
of breast cancer. Key aspects and limitations of standard treatments are discussed. In ad-
dition, the importance of customizability is underlined. An overview of 3DP and 4DP
technologies, materials employed, associated advantages, and challenges is provided. In
addition, sections dedicated to recent 3DP and 4DP applications in the fight against breast
cancer are reported with regard to treatment and surgery-related approaches. Finally, reg-
ulatory aspects and future perspectives are discussed.
Figure 1. Schematic illustration of breast cancer progression.
The growth and development of the mammary gland are dependent on complex
interactions between hormones (estrogen and progesterone) and growth factors (human
epidermal HER2) with their specific cellular receptors [
10
]. Estrogen stimulates the normal
growth of ducts, while progesterone is responsible for the development of the lobule and
alveolar. These lipophilic molecules easily diffuse through the membrane and bind to the
receptors present in the cytoplasm that are transported to the nuclei where they interact
with the DNA. This interaction will stimulate the genetic response that affects the normal
growth of the cell and its function. Thus, knowing the expression of hormones of the tumor
is important, as it allows for predicting the prognosis and the possible response to the
endocrine treatment and selecting the adequate therapy [6,11].
Conventionally, breast cancer can be classified according to the presence or absence of
three biomarkers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal
growth factor receptor 2 (HER2), being called hormone receptor-positive or negative.
However, the expression of ER, PR, and HER2 receptors is not universal; around 15–20% of
breast cancers are hormone receptor-negative, called triple-negative breast cancers (TNBCs).
TNBC is an invasive cancer subtype, characterized by aggressive behavior, early relapse,
and metastases; in addition, TNBC does not respond to conventional treatments, limiting
the survival of patients [12,13].
Breast cancer not only concerns the potential survival of patients but also their well-
being, from the aesthetic and emotional point of view. During the last decade, efforts have
been made to improve the quality of life of patients and survivors by making progress in
the prevention, diagnosis, and treatment of this burden of disease.
This review article encompasses an overview of current strategies in the management
of breast cancer. Key aspects and limitations of standard treatments are discussed. In
addition, the importance of customizability is underlined. An overview of 3DP and 4DP
technologies, materials employed, associated advantages, and challenges is provided. In
addition, sections dedicated to recent 3DP and 4DP applications in the fight against breast
cancer are reported with regard to treatment and surgery-related approaches. Finally,
regulatory aspects and future perspectives are discussed.
2. Principles of Therapy for Breast Cancer: Current Treatments and Limitations
The treatment for breast cancer varies according to the clinical and pathological staging.
Moreover, considering the options available and the physiological impact of treatments,
the selection of the appropriate strategy should include the patient’s wishes (for instance,
Biosensors 2022,12, 568 3 of 20
choosing between breast-conserving surgery or mastectomy) [
14
]. Indeed, the treatment
aims to obtain satisfactory results from the aesthetical point of view, without compromising
the control over the tumor or the survival of the patient. Commonly, the initial phase of the
treatment involves surgery and radiotherapy; systemic therapies are sometimes necessary,
which will be discussed in this section.
2.1. Surgery and Radiotherapy
Surgery is performed to resect the primary tumor with the surrounding margin with or
without a staging of the axillary lymph nodes. The possibility of performing a satisfactory
resection depends on the dimensions and localization of the tumor, the dimensions of the
breast, and the necessary margin. Different types of surgery can be performed according
to the objective to be achieved. When the tumor is identified, breast conserving surgery
or mastectomy can be chosen. In addition, radiotherapy can be necessary to eradicate the
residual disease and prevent recidivism [15].
Breast-conserving surgery is the primary treatment, usually associated with radiother-
apy. The volume of excised breast and skin should be the minimum possible to preserve
normal tissue and shape. Breast-conserving surgery requires a careful assessment of the
mammography before the biopsy and the localization of the tumor concerning the margins
of the excision. The evaluation of the margin of a sample of excision is fundamental to
predicting recurrence and prognosis; however, it can be difficult because an error in the
sampling can occur, and there are not standardized methods. If the margins of the exci-
sion are clear, the patient can be treated with radiotherapy [
16
]. Radiotherapy employs
high-energy X-rays or gamma rays to kill cancer cells, reduce the risk of local recidivism,
and avoid short- and long-term complications. According to the area affected by cancer,
radiation can be focused on a specific site or the entire breast. Standard treatments are
administered five days a week for a period of six or seven weeks [
17
]. Alternatively, if
margins are positive, mastectomy will be performed. During a mastectomy, the nipple
and areola will be removed, significantly impacting patients’ well-being. For this reason,
patients are encouraged to undergo to the immediate reconstruction of the removed tissues,
although this additional surgery will prolong the hospitalization [16].
Breast Reconstruction
Breast reconstruction can be necessary to reshape the breast; the removal of a big tumor
can result in breast deformation and dimpling formation, affecting the patient’s wellbeing.
The currently available reconstructive technique cannot re-establish the physiological
function of the mammary gland but can help breast cancer survivors to restore their
body image and thus their self-confidence. Generally, two options are available for the
reconstruction: artificial implants or autologous tissue flaps reconstruction; both techniques
can sometimes be performed together to achieve better results [18].
Implants are inserted under the pectoralis major muscle or under the breast gland;
an expander is sometimes necessary to create the pocket under the muscle and allow skin
stretch. They are generally made of an outer shell of silicone and filled with different
materials, commonly with silicone gel or sterile salt water. The size, shape, and surface
(rough or smooth) can be chosen according to the patient’s needs [
19
,
20
]. The employment
of implants presents some advantages as the surgery is rapid and the result is aesthetically
pleasing. However, downsides are related to possible infections that require the removal of
the implant, capsular contracture, implant dislocation, or deformities [
21
,
22
]. Otherwise,
tissue-based reconstruction can be performed. This procedure consists of rebuilding the
breast shape using tissue from the patient’s body, usually from the abdomen, back, or
gluteus. The main drawback of this technique is that tissue undergoes natural changes,
for instance, weight loss or gain; in addition, the recovery is longer, and the procedure
is more complex [
23
,
24
]. The final step of reconstruction concerns the nipple–areola area.
Reconstruction of this area can be done by surgery or tattooing. However, women that
do not wish or are not good candidates to undergo surgery opt for the employment of an
Biosensors 2022,12, 568 4 of 20
external prosthesis that can simulate the natural shape of the breast and/or nipple. The
prosthesis can be attached to the bra or can be directly applied to the body through an
adhesive band. Usually, external prostheses are made of silicone, and different shapes,
sizes, and color tones are available [25,26].
2.2. Systemic Therapy
Systemic therapy is often recommended to prevent recidivism and prolong a patient’s
survival. It concerns chemotherapy, consisting of a specific cytotoxic compound, and
hormonal therapy, based on the modification of the endocrine environment to influence the
tumor cells’ growth. Systemic therapy can be administered before the surgery (neoadjuvant
chemotherapy) to reduce the size of the tumor or after the surgery (adjuvant chemotherapy)
to kill residual cancer cells and prevent recurrences. The potential toxicity of treatments
must be considered within the advantages conferred [27,28].
2.2.1. Chemotherapy
Chemotherapeutic drugs interfere with the fundamental cellular processes, provoking
cell death. Even if drugs have pleiotropic effects, they can be distinguished according
to their primary mechanism of action. Drugs that interfere with the DNA replication act
through the alkylation of the base pair of the DNA or by interposing in the double helix of
the DNA. Cytotoxicity can be also obtained by altering the integrity of the membrane and
impeding the normal homeostasis. For the treatment of breast cancer, commonly alkylating
agents, anthracycline (e.g., doxorubicin), antimetabolites (e.g., 5-fluorouracil), and some
vinca alkaloids (e.g., vinblastine) are employed. Chemo drugs are often administered in
combination as an injection or infusion. The duration of treatment depends on the drug
employed and on individual response to it; generally, it ranges from 3 to 6 months in total.
Chemotherapy is not specific for tumor cells; the drugs act when cells are in the active
phase of the cell cycle. The most common collateral effects are related to the gastrointestinal
system (nausea, vomiting, and diarrhea) and hair loss [6,27,28].
2.2.2. Endocrine Therapy
Hormone receptor-positive breast cancer cells are sensitive to hormonal therapy (or
endocrine therapy). Therapeutic effects are related to the reduction of the production of
estrogen (e.g., ovarian suppression or aromatase inhibitor) or the block of the estrogen
effects at a cellular level (e.g., tamoxifen). Ovarian suppression can be achieved by causing
temporary menopause using luteinizing hormone-releasing hormone (LHRH) agonist or
chemo drugs, or permanently by removing the ovaries (oophorectomy). Another strategy
is represented by an aromatase inhibitor, a class of drugs that target the enzyme aromatase,
responsible for the production of estrogen. Currently, HER2-2 positive breast cancer
can be treated with monoclonal antibodies (e.g., trastuzumab) eventually linked with
chemotherapy drugs (e.g., ado-trastuzumab emtansine; the monoclonal antibody allows
the target delivery of the chemo drug) or with kinase inhibitors (e.g., lapatinib). Generally,
the choice of the treatment varies according to if the woman is pre- or post-menopause. A
combination of both types of systemic treatments can be an option, usually for a duration
of 5 to 10 years. Side effects associated with endocrine therapy are milder than those
of chemotherapy and usually include hot flashes, vaginal dryness, and changes in the
menstrual cycle [6,27,29].
However, standard therapies often present limitations such as poor bioavailability,
short-term efficacy due to drug resistance, a propensity to relapse, and poor prognosis.
In addition, the great variability between individuals and tumors results in a different
response to treatment. Therefore, the need for alternative strategies is urgent. Table 1
summarizes the main advantages and disadvantages of conventional therapies.
Biosensors 2022,12, 568 5 of 20
Table 1.
Advantages and disadvantages of current standard therapies for the treatment of breast cancer.
Treatment Advantages Disadvantages
Surgery
Breast conserving Not invasive,
preserves the natural shape of the breast. Possibility of recurrence.
Mastectomy Lowers the chance of recurrence.
Invasive,
poor cosmetic outcome,
high emotional impact.
Systemic Therapy
Chemotherapy
Before surgery facilitates the removal of the
tumor and enables a less invasive procedure,
lower chance of metastasis and recurrence.
Unpleasant side effects (e.g.,
nausea, fatigue, hair loss).
Endocrine Therapy
Milder side effects than chemotherapy,
possibility to combine it with chemotherapy
or radiotherapy to achieve better results.
Limited to hormone
receptor-positive breast cancer,
higher possibility of resistance
to treatment,
early menopause.
3. Personalized Medicine and Additive Manufacturing
Currently, industry’s pillars are no longer rooted in mass production; they are pri-
oritizing more and more individual needs, marking a new manufacturing era based on
demand. Personalized medicine (PM) is a continuously expanding approach that can be
applied in the diagnosis, treatment, and prevention of several diseases. Based on indi-
vidual differences (e.g., biochemical and genomics), lifestyle and environment, and their
contribution to the clinical outcomes, PM allows the selection of the ideal clinical path
for the specific patient [
30
,
31
]. Considering the high heterogeneity of tumors and unique
individuality that lead to different treatment responses, PM can represent a promising and
beneficial strategy to tailor patient-centric therapies, thus achieving successful results in
cancer treatment [
32
,
33
]. The realization of PM can be achieved by additive manufacturing
(AM) technology [32,34].
AM encompasses a group of technologies that allow the production of complex ob-
jects in a layered fashion using computer-aided control [
35
]. Three-dimensional printing
technologies are classified into seven categories (illustrated in Figure 2): material extrusion,
binder jetting, photopolymerization, material jetting, powder bed fusion, sheet lamination,
and directed energy deposition [
36
]. Table 2reports, for each category, the techniques in-
cluded, a brief description of the printing process, and their strengths and weaknesses [
37
].
The possibility of easy customization is one of the key aspects of 3DP; considering
pharmaceuticals, it allows the production of a variety of dosage forms, tailored according
to the patient’s profile. The personalization of the product may concern the shape, the size,
and the drug dose. Moreover, a combination of drugs (e.g., polypills) and drug release
rate can be customized, resulting in the reduction of side effects and improvement of the
adherence and compliance of the patient [3941].
The continuous evolution of 3DP led to the introduction of a fourth dimension, time.
Tibbits first introduced 4DP in 2013 during his Technology, Entertainment, and Design
(TED) Talk conference [
42
]. This technology can be defined as the manufacturing of dynamic
3D printed objects able to change their morphology and/or characteristics as a function of
time. The self-transformation, which should be predictable and programmable, is provided
by one or more external stimuli, such as the variation in the pH, temperature, humidity, light,
or the presence of a magnetic field. The stimulus is selected according to the final application,
and it will affect the material choice. Common transformations are related to shape-shifting
abilities, such as folding, bending, twisting, expansion, and shrinkage, while property changes
include the color, the stiffness, and the swelling ratio [
43
45
]. This is achieved by using
stimuli-responsive materials, also called “smart materials”, which are discussed in Section 4.2.
Four-dimensional printing is a booming technology that requires multiple expertise including
chemistry, engineering, and mathematical and computational modeling. This advanced
research approach is trusted to revolutionize the future of the manufacturing process and
Biosensors 2022,12, 568 6 of 20
daily life of a wide spectrum of fields, including electronics, aerospace, and engineering [
46
].
Although its application in the biomedical and pharmaceutical fields is still in the early stages,
research is highlighting its enormous potential, especially in expanding the possibilities of
personalization [47].
The following sections will focus on current trends and future applications of 3DP and
4DP in the diagnosis, treatment, and prevention of breast cancer.
Biosensors 2022, 12, x FOR PEER REVIEW 6 of 22
Figure 2. Schematic representation of 3DP techniques, reproduced with permission from Elsevier,
license number 5334150461456 [38].
Table 2. Three-dimensional printing techniques, brief description of the printing process,
strengths, and weaknesses.
Category
Technique
Brief Description
Strengths
Weaknesses
Material
Extrusion
Fused deposition
modeling (FDM);
direct ink writing (DIW)
Thermoplastic
materials or semi-solid
inks are extruded
through a nozzle.
Good variety of
materials, low
costs.
Low resolution and time
consuming.
Binder Jetting
The build material, in
the form of powder,
and the binder
material, generally
liquid, are alternatively
deposited into the
printing bed.
Scalability, high
speed.
Poor accuracy, post processing.
Photopolymeriz
ation
Stereolithography (SLA);
digital light processing
(DLP)
The final object is
obtained through a
chemical reaction
(photopolymerization)
triggered by
irradiation.
High accuracy,
high speed.
Limited material availability
(photo-resins), high costs, post
processing.
Material Jetting
Material is deposited
dropwise or
continuously onto the
printing bed through a
printing head.
Low cost, high
speed,
scalability.
Limited material availability
(polymers or waxes), support
necessary.
Figure 2.
Schematic representation of 3DP techniques, reproduced with permission from Elsevier,
license number 5334150461456 [38].
Table 2.
Three-dimensional printing techniques, brief description of the printing process, strengths,
and weaknesses.
Category Technique Brief Description Strengths Weaknesses
Material Extrusion Fused deposition modeling (FDM);
direct ink writing (DIW)
Thermoplastic materials or
semi-solid inks are extruded
through a nozzle.
Good variety of materials,
low costs.
Low resolution and time
consuming.
Binder Jetting
The build material, in the
form of powder, and the
binder material, generally
liquid, are alternatively
deposited into the printing
bed.
Scalability, high speed. Poor accuracy, post
processing.
Photopolymerization Stereolithography (SLA);
digital light processing (DLP)
The final object is obtained
through a chemical reaction
(photopolymerization)
triggered by irradiation.
High accuracy, high speed.
Limited material
availability
(photo-resins), high costs,
post processing.
Material Jetting
Material is deposited
dropwise or continuously
onto the printing bed through
a printing head.
Low cost, high speed,
scalability.
Limited material
availability (polymers or
waxes), support
necessary.
Powder Bed Fusion
Direct metal laser sintering (DMLS);
selective laser melting (SLM);
electron beam melting (EBM);
selective heat sintering (SHS);
selective laser sintering (SLS)
Laser or electron beams are
applied as thermal source to
melt powder particles and
build the device.
Good resolution, wide range
of materials, complexity of
the design achieved.
Small product size, high
cost, time consuming.
Biosensors 2022,12, 568 7 of 20
Table 2. Cont.
Category Technique Brief Description Strengths Weaknesses
Sheet Lamination Ultrasonic additive manufacturing (UAM);
laminated object manufacturing (LOM)
The material, in the form of
sheets, is cut by a laser
according to the desired
design. Each layer is bonded
by pressure, temperature, or
adhesive coating.
Low costs, robust.
Low resolution and poor
accuracy, post
processing.
Direct Energy
Deposition
Direct light fabrication (DLF);
laser engineered net shaping (LENS);
direct metal deposition (DMD)
Powder or wire material and
the substrate are
simultaneously melted using
an energy source (laser or
electron beam). Firstly, the
substrate will create the melt
pool where the material will
be deposited.
Production of dense part with
microstructures, ability to
control the structure.
Post-processing, time
consuming, low material
availability.
4. Three-Dimensional and Four-Dimensional Printing
4.1. Advantages and Disadvantages
Nowadays, 3DP benefits are well established, especially when compared with the
traditional manufacturing process. Among many advantages, rapid prototyping, ease of
accessibility, structural control, and cost-effectiveness are the most considered. Moreover,
from the environmental perspective, 3DP shows eco-friendly features, as it reduces waste
production, chemicals are not necessary, and the production process requires low energy.
Nevertheless, its real-life application is restrained due to some limitations such as the
restricted build size, post-processing, and lack of regulation. Both the advantages and
limitations are automatically translated to 4DP [
48
,
49
]. The introduction of the fourth
dimension has led to a higher level of breakthrough, particularly in terms of product com-
plexity and customization possibilities. The dynamism, combined with the programmed
functionalities, is a key advantage of 4DP. However, there are challenges that should be
faced, related to materials, technical aspects, and the design process. Since smart materials
are the core of 4DP technology, increasing the availability and gaining a better understand-
ing of the impact of the material properties should be prioritized. More attention should
be focused on new materials and on improving the biocompatibility and printability of
the currently available materials. Expertise in the materials’ properties and their behavior
will enable the design process to be more precise, resulting in higher alteration accuracy
and advancements in the potential applications. Furthermore, new triggering mechanisms
should be explored to produce faster responses and expand their applications. In the case
of biomedical research, sensitiveness to specific biological molecules (e.g., the presence
of glucose or enzymes) can increase
in vivo
feasibility [
50
]. Robust, efficient, and highly
sensitive methods need to be developed to improve the manufacturing quality of the
printing process of smart materials, together with the development of theoretical models
and design methodologies [51,52].
4.2. Materials for 3DP and 4DP
The materials used in AM differ in physical and mechanical properties. The selection
of the materials varies according to the technique employed and the desired final products.
Printing materials can be liquid, paste, powder, or solid sheets. They include polymers,
ceramics, metals, resins, and even food [
53
55
]. Table 3outlines the most common materials
employed in breast cancer applications and their main characteristics.
However, most 3DP materials are not applicable for 4DP. Thus, taking inspiration
from nature, efforts have been made to fulfill the need [56].
Four-dimensional printing is based on the employment of a so-called smart material
or programmed material. The term smart material indicates a material’s adeptness at
changing its function and/or shape upon stimulation, as a change in the physiological
parameters or external factors. The choice of the appropriate material is one of the main
steps when approaching 4DP, together with the choice of the optimal printing technique and
the adequate stimulus. Currently, smart materials can be distinguished between polymers,
Biosensors 2022,12, 568 8 of 20
ceramics, alloys, composites, and metals. Moreover, they can be classified according to
the endowed properties, including self-repairing, shape-changing, self-sensing, or self-
assembling [
57
,
58
]. Smart materials can undergo single or multiple changes, that can be
programmed as one-way or two-way. One-way transformations are planned to retain
the triggered alteration while the two-way transformations are reversible. Furthermore,
changes can be repeatable. Nevertheless, the range of available materials needs to be
expanded in order to increase the implementation of 4DP; thus, research is required to
focus on the compatibility and design of precise responsive materials [51].
Table 3. Most common AM materials applied for breast cancer and their main characteristics.
Material Characteristics Breast Cancer Application
Polycaprolactone
(PCL)
Low melting temperature,
slow degradation rate,
good mechanical properties.
Scaffold to guide breast reconstruction
and drug delivery.
Polylactic acid
(PLA)
flexible,
slow degradation rate. Nipple–areola complex scaffold.
Poly(lactic-co-glycolic acid)
(PLGA)
High degradation rate.
High mechanical strength,
good processability,
high melting temperature.
Scaffold for drug delivery.
Herein, the focus will be on shape-changing materials, specifically shape memory
materials and smart hydrogels.
4.2.1. Shape Memory Materials
The response to a specific trigger can be expressed through several transformations;
among these, shape shifting has attracted great attention. When considering shape shifting,
it is important to distinguish between a shape-changing effect and shape memory effect.
Indeed, the first case describes the ability to deform to a temporary shape that is immedi-
ately restored when the driving stimulus is removed. On the contrary, the shape memory
effect defines the ability to deform to a temporary shape that is maintained over time and
can recover back to the original form in response to specific external stimulation. Thus,
the shape memory effect can be described by two factors: the shape fixity ratio (ability to
maintain the temporary shape) and the shape recovery ratio (efficiency in recovering the
original shape). Furthermore, multiple temporary shapes can be sequentially acquired [
43
].
Different shape memory materials have been developed: a brief description of alloys
and polymers is provided in the following sections.
Shape Memory Alloys
The shape memory effect for alloys is based on the reversible transformation between
two crystalline phases: austenite and martensite, each of which is characterized by distinc-
tive characteristics. The austenitic phase presents a cubic structure; while the martensitic
structure varies according to the alloy composition (e.g., tetragonal, orthorhombic, or mon-
oclinic structure). Moreover, different martensitic orientations can be observed, which are
called variants. If one variant prevails, the martensite is called “detwinned”, whereas if
combinations of variants coexist, it will be called twinned martensite. The shape memory
effect is mainly activated by heat. The austenitic phase represents the initial phase that is
subject to deformation upon cooling at the martensitic start temperature (Ms) and will be
fully transformed to twinned martensite at the martensitic finish temperature (Mf). The
recovery to austenite is initiated at the austenitic start temperature (As) and will take place
at the austenitic finish temperature (Af). Moreover, when sufficient stress is applied to the
martensitic phase, the detwinning process can occur, resulting in temporary deformation
of the orientations (Figure 3). The detwinned orientation can be preserved even when the
stress is released. Currently, the most investigated alloys are copper, nitinol-titanium (NiTi),
Biosensors 2022,12, 568 9 of 20
iron, and their combination with other materials. Among them, NiTi systems are the most
explored, because of the better biocompatibility, good processability, and good properties,
such as the high actuation stress and recoverable strain. However, due to their complex
production, high cost, potential toxicity, and limited recovery, other materials are preferred
over alloys [5961].
Figure 3.
Shape memory effect of alloys, reproduced with permission from Elsevier, license number
5334150011086 [62].
Biosensors 2022,12, 568 10 of 20
Shape Memory Polymers (SMPs)
SMPs are wildly employed for 4DP applications because of their favorable properties,
including their low cost, light weight, good manufacturability, high flexibility, and defor-
mation ability. When the transformation is induced by heat, materials are called thermally
responsive. Commonly, the shape transformation occurs by heating above the transition
temperature at which the polymer chains can easily move due to the increase in entropy.
By applying an external force, the printed object shifts to a temporary shape, characterized
by lower entropy, thus reducing mobility. The rearrangement is fixed by cooling below the
transition temperature. When removing the external force, the temporary shape is retained
until heating again above the transition temperature, at which point the original shape will
be spontaneously recovered. This programming process can be repeated, and different tem-
porary shapes can be obtained (Figure 4) [
58
,
62
]. In the biomedical field, thermo-responsive
polymers are the most investigated materials. Among them, PLA showed to be a promising
candidate for 4DP applications, in particular to produce vascular stents [
63
,
64
] and bone
tissue scaffolds [
65
,
66
], allowing minimal invasive surgery. However, some drawbacks
limit the use of polymers in 4DP, for instance, the strength and stiffness [
67
]. For this reason,
combinations of materials can sometimes represent an opportunity to improve materials’
properties; alternatively, newly synthesized materials should be investigated.
Biosensors 2022, 12, x FOR PEER REVIEW 11 of 22
deformation ability. When the transformation is induced by heat, materials are called ther-
mally responsive. Commonly, the shape transformation occurs by heating above the tran-
sition temperature at which the polymer chains can easily move due to the increase in
entropy. By applying an external force, the printed object shifts to a temporary shape,
characterized by lower entropy, thus reducing mobility. The rearrangement is fixed by
cooling below the transition temperature. When removing the external force, the tempo-
rary shape is retained until heating again above the transition temperature, at which point
the original shape will be spontaneously recovered. This programming process can be
repeated, and different temporary shapes can be obtained (Figure 4) [58,62]. In the bio-
medical field, thermo-responsive polymers are the most investigated materials. Among
them, PLA showed to be a promising candidate for 4DP applications, in particular to pro-
duce vascular stents [63,64] and bone tissue scaffolds [65,66], allowing minimal invasive
surgery. However, some drawbacks limit the use of polymers in 4DP, for instance, the
strength and stiffness [67]. For this reason, combinations of materials can sometimes rep-
resent an opportunity to improve materialsproperties; alternatively, newly synthesized
materials should be investigated.
Figure 4. Shape memory effect of polymersreproduced with permission from Elsevier, license num-
ber 5334150884441 [68].
4.2.2. Smart Hydrogels
Hydrogels are hydrophilic materials that, according to their origin, can be synthetic
or derived from nature. Natural hydrogels comprise polysaccharides, such as alginate,
chitosan, hyaluronic acid, and cellulose, and proteins, such as gelatin and collagen. Syn-
thetic hydrogels can be a homopolymer (one monomer); copolymer (made of two co-mon-
omer units); or multipolymer (composed of three or more co-monomer units). Among the
synthetic polymers, polyacrylamide, polyethylene glycol (PEG), and acryl acid are the
most common [69,70]. Hydrogels are suitable for 4DP purposes, especially for the shape-
morphing transition, because of their intrinsic swelling ability. Indeed, when exposed to
a stimulus, they can undergo volume modifications, such as swelling and shrinkage, or
Figure 4.
Shape memory effect of polymersreproduced with permission from Elsevier, license number
5334150884441 [68].
4.2.2. Smart Hydrogels
Hydrogels are hydrophilic materials that, according to their origin, can be synthetic or
derived from nature. Natural hydrogels comprise polysaccharides, such as alginate, chi-
tosan, hyaluronic acid, and cellulose, and proteins, such as gelatin and collagen. Synthetic
hydrogels can be a homopolymer (one monomer); copolymer (made of two co-monomer
units); or multipolymer (composed of three or more co-monomer units). Among the
synthetic polymers, polyacrylamide, polyethylene glycol (PEG), and acryl acid are the
most common [
69
,
70
]. Hydrogels are suitable for 4DP purposes, especially for the shape-
Biosensors 2022,12, 568 11 of 20
morphing transition, because of their intrinsic swelling ability. Indeed, when exposed
to a stimulus, they can undergo volume modifications, such as swelling and shrinkage,
or structural modifications such as sol/gel transition [
71
]. This change can be exploited
for drug delivery purposes. Recently, Zu et al. developed a poly(N-isopropylacrylamide)
(PNIPAM)-based capsule shell for smart controlled drug release. The presence of PNIPAM
introduced temperature responsiveness; thus, the controlled drug release can be attributed
to the modification of the internal pore size, achieved by the variation of the temperature
above or below the lower critical solution temperature (LCST) [
72
]. However, hydrogels
show some limitations in terms of mechanical strength, stability, and manipulation possi-
bilities. For this reason, they are often crosslinked with polymers. In 4DP, the printed object
can be completely responsive, or the structure can comprise active and passive components.
Commonly, hydrogels are crosslinked with non-responsive polymers in order to create a
layered platform: the hydrogel will form the active layers, able to absorb water and swell,
while the passive layers will be made of the polymer. The deformation is adjusted by
varying the distribution of the two layers. This mechanism is commonly used to create
self-folding devices. However, the deformation is not defined and the response requires
time [49,58].
5. Three-Dimensional Printing in the Fight against Breast Cancer
Three-dimensional printing has shown a significant impact in revolutionizing the
standard conception of illness and treatment. In breast cancer, its potential clinical signifi-
cance encompasses all aspects, including the diagnosis, treatment, and aesthetic outcome.
The following sections will provide an overview of current applications of 3DP in the
fight against breast cancer. Despite some tools to diagnose breast cancer that have been
developed [7375], this review will focus on treatment and surgery-related applications.
5.1. Three-Dimensional-Printed Prototypes
Breast and tumor prototypes are key instruments used for different purposes, includ-
ing diagnostic tasks, surgery training, preoperative planning, treatment optimization, and
drug screening. Three-dimensional-printed physical phantoms are employed to mimic the
patient’s anatomy, both from the external and internal perspectives, allowing the evaluation
and optimization of imaging techniques [
76
,
77
]. In addition, they can be useful to predict
the dose distribution for safe and effective radiotherapy treatments [
78
]. Three-dimensional-
printed models can additionally help surgeons to plan and make decisions, as well as be
employed for training activities or to increase the efficacy of patient communication [
79
].
From a practical perspective, 3DP tumor models were developed to localize the tumor,
providing a physical model of the area in order to facilitate and guide the resection. For
this purpose, breast images are fundamental to acquiring necessary information enabling
the production of an accurate design. Wu et al. reported the application of MRI-based
patient-specific 3DP surgical guides (Figure 5) for breast-conserving surgery in patients
with ductal carcinoma in situ and invasive ductal carcinoma. In both case studies, the
results suggested that surgery was successfully performed with clear margins [80,81].
Biosensors 2022, 12, x FOR PEER REVIEW 12 of 22
structural modifications such as sol/gel transition [71]. This change can be exploited for
drug delivery purposes. Recently, Zu et al. developed a poly(N-isopropylacrylamide)
(PNIPAM)-based capsule shell for smart controlled drug release. The presence of
PNIPAM introduced temperature responsiveness; thus, the controlled drug release can
be attributed to the modification of the internal pore size, achieved by the variation of the
temperature above or below the lower critical solution temperature (LCST) [72]. However,
hydrogels show some limitations in terms of mechanical strength, stability, and manipu-
lation possibilities. For this reason, they are often crosslinked with polymers. In 4DP, the
printed object can be completely responsive, or the structure can comprise active and pas-
sive components. Commonly, hydrogels are crosslinked with non-responsive polymers in
order to create a layered platform: the hydrogel will form the active layers, able to absorb
water and swell, while the passive layers will be made of the polymer. The deformation
is adjusted by varying the distribution of the two layers. This mechanism is commonly
used to create self-folding devices. However, the deformation is not defined and the re-
sponse requires time [49,58].
5. Three-Dimensional Printing in the Fight against Breast Cancer
Three-dimensional printing has shown a significant impact in revolutionizing the
standard conception of illness and treatment. In breast cancer, its potential clinical signif-
icance encompasses all aspects, including the diagnosis, treatment, and aesthetic outcome.
The following sections will provide an overview of current applications of 3DP in the fight
against breast cancer. Despite some tools to diagnose breast cancer that have been devel-
oped [7375], this review will focus on treatment and surgery-related applications.
5.1. Three-Dimensional-Printed Prototypes
Breast and tumor prototypes are key instruments used for different purposes, includ-
ing diagnostic tasks, surgery training, preoperative planning, treatment optimization, and
drug screening. Three-dimensional-printed physical phantoms are employed to mimic
the patient’s anatomy, both from the external and internal perspectives, allowing the eval-
uation and optimization of imaging techniques [76,77]. In addition, they can be useful to
predict the dose distribution for safe and effective radiotherapy treatments [78]. Three-
dimensional-printed models can additionally help surgeons to plan and make decisions,
as well as be employed for training activities or to increase the efficacy of patient commu-
nication [79]. From a practical perspective, 3DP tumor models were developed to localize
the tumor, providing a physical model of the area in order to facilitate and guide the re-
section. For this purpose, breast images are fundamental to acquiring necessary infor-
mation enabling the production of an accurate design. Wu et al. reported the application
of MRI-based patient-specific 3DP surgical guides (Figure 5) for breast-conserving sur-
gery in patients with ductal carcinoma in situ and invasive ductal carcinoma. In both case
studies, the results suggested that surgery was successfully performed with clear margins
[80,81].
Figure 5. Patient-specific surgical guides [80,81].
Biosensors 2022,12, 568 12 of 20
5.2. Three-Dimensional Printing Application in the Treatment of Breast Cancer
Drug-Loaded Implants
As previously discussed, traditional treatments for breast cancer include surgery,
radiotherapy, and systemic therapy. However, these strategies have limitations, underlining
the need for alternative therapies. A drug-loaded implant can represent a promising option
to efficiently control local drug delivery and reduce side effects. Indeed, implants allow
the reduction of dose and frequency of drug administration, resulting in minimal systemic
toxicity. Moreover, multiple drugs can be loaded into the same device, enabling a synergic
effect. Implants can be inserted near the tumor, to deliver chemotherapy drugs, or after
the surgery resection to prevent recurrence and metastasis. Three-dimensional-printed
implants for breast cancer treatment can be designed in a variety of geometries using
different materials and drugs. For instance, Dang et al. produced a porous PCL implant
loaded with doxorubicin (DOX) [
82
], while Fan et al. reported the manufacturing of
an ultrahigh-molecular-weight-polyethylene scaffold loaded with 5-fluorouracil (5-FU)
using the FDM technique [
83
]. Quiao et al. developed, by material jetting, poly-lactic-
co-glycolic acid (PLGA)-based implants to simultaneously deliver the combination of
drugs in a controlled manner. In an earlier study, they investigated the effect of DOX and
cisplatin, and later that of 5-FU and NVP-BEZ235.
In vitro
and
in vivo
studies showed
promising results in suppressing tumor growth, suggesting the benefit of these drug
delivery systems [
84
,
85
]. PLGA was also employed by Shi et al. to manufacture, through
material jetting, a multifunctional device with the aim to inhibit cancer growth and provide
wound healing. For this purpose, DOX and 5-FU were chosen as therapeutic compounds,
while gelatin crosslinked with chitosan was added to promote wound healing and tissue
regeneration and to confer pH responsiveness.
In vitro
and
in vivo
studies confirmed the
hemostasis ability, blood absorption, and wound healing ability. In addition, the controlled
delivery of drugs was achieved [
86
]. Multipurpose implants can promote anticancer
activity and, simultaneously, tissue repair as additionally suggested by Luo et al. Moreover,
they investigated the possibility of monitoring the implant performance during
in vivo
imaging by incorporating Mn
2+
ions and polydopamine (PDA) to the bioprinted device [
87
].
Furthermore, 3DP technology offers the opportunity to produce advanced devices: He
et al. combined a 3DP bio-glass scaffold with an immune adjuvant to treat bone metastasis
of breast cancer. The device consisted of the incorporation into the scaffold of a niobium
carbide (Nb2C) MXene nanosheet coated with mesoporous silica, loaded with R837 (an
immune adjuvant). The resulting product possessed photothermal and immune activation
properties, able to attack the tumor and avoid metastasis and recurrences. In addition,
the implant supported osteogenesis. Overall, the authors believe that their study could
represent a promising strategy to produce in situ tumor vaccines [88].
5.3. Three-Dimensional Printing Application in Breast Reconstruction
5.3.1. Scaffold-Guided Reconstruction
Nowadays, a variety of reconstructive strategies are available, with the aim to re-
establish the self-confidence of patients post-mastectomy. One strategy is represented by
the development of a 3D scaffold able to guide cellular interaction and tissue formation.
Ideally, the scaffold should match the natural mechanical properties of the breast, allow
tissue regeneration, and maintain a pleasing cosmetic shape of the breast. An additional
feature is represented by the possibility to stimulate the adipose tissue by incorporating
adipose-derived stem cells (ADSCs) into the device. The design of the product is tailored
according to images captured by computed tomography or magnetic resonance, in order to
meet the patient’s needs [
89
93
]. Among the materials suitable to produce 3DP scaffolds,
PCL has been largely employed owing to its beneficial properties, such as biocompatibility,
good processability, and good mechanical properties. In 2016, Chhaya et al. implanted a
PCL-made scaffold in minipigs and compared the effect of the empty scaffold, the scaffold
loaded with lipoaspirate, and the scaffold in which the autologous fat was injected after
14 days
of implantation. After 24 weeks, angiogenesis and adipose tissue regeneration were
Biosensors 2022,12, 568 13 of 20
observed, in particular for the device with delayed injection, suggesting the potentiality
of this technique (Figure 6) [
94
]. With the aim to better control fat distribution, in 2019,
the same group developed, by FDM, a complex design composed of independent internal
and external structures. The geometry of the internal structure was designed to guide
tissue regeneration, being modified according to the patient’s profile, while the external
structure provided biomechanical support [
95
]. The potentiality of 3DP scaffolds in fat
grafting was additionally suggested by Bao et al. Nonetheless, they underlined the need
for optimization related to the ability to efficiently provide vascularization and to the
long degradation profile of the product [
96
]. Thus, to improve the
in vivo
performance
of 3DP scaffolds, different aspects should be considered. Zhou et al. emphasized the
importance of the design on the mechanical properties of the final product, fundamental
to mimicking the native breast characteristics [
97
]. Given the importance of resembling
the natural breast properties, Tytgat et al. focused on the development of soft scaffolds,
using a material extrusion-based 3D printer. Studies confirmed similarities between the
manufactured devices and native tissue. Moreover, scaffolds were able to support ADSCs
differentiation [
98
]. As previously mentioned, one of the main advantages of the 3DP
technique is its versatility. This advantage was exploited by Dang et al., who combined
breast regeneration with the possibility of simultaneously administering the drug to prevent
surgical complications. Indeed, in the proof-of-concept study, they developed by FDM
a PCL scaffold able to guide tissue regeneration. The scaffold was subsequently loaded
with chemotherapeutic drugs (DOX and paclitaxel) and antibiotics (cefazolin) to prevent
recurrence and infection [
99
]. In 2017, two start-ups were launched, aiming to provide a
valid alternative to silicone prostheses. LATTICE MEDICAL developed a bioprosthesis,
called MAT(T)ISSE, using the FDM technique. MAT(T)ISSE provides volume to the breast
and allows adipose tissue regeneration. In addition, it degrades in one year, requiring only
one surgery [
100
]. The company BELLASENO manufactured a PCL resorbable scaffold
that completely degrades in 2–3 years. The product, called SENELLA BREAST, is designed
to be employed for breast reconstruction and augmentation, and it allows fat injection [
101
].
Biosensors 2022, 12, x FOR PEER REVIEW 14 of 22
implanted a PCL-made scaffold in minipigs and compared the effect of the empty scaf-
fold, the scaffold loaded with lipoaspirate, and the scaffold in which the autologous fat
was injected after 14 days of implantation. After 24 weeks, angiogenesis and adipose tis-
sue regeneration were observed, in particular for the device with delayed injection, sug-
gesting the potentiality of this technique (Figure 6) [94]. With the aim to better control fat
distribution, in 2019, the same group developed, by FDM, a complex design composed of
independent internal and external structures. The geometry of the internal structure was
designed to guide tissue regeneration, being modified according to the patient’s profile,
while the external structure provided biomechanical support [95]. The potentiality of 3DP
scaffolds in fat grafting was additionally suggested by Bao et al. Nonetheless, they under-
lined the need for optimization related to the ability to efficiently provide vascularization
and to the long degradation profile of the product [96]. Thus, to improve the in vivo per-
formance of 3DP scaffolds, different aspects should be considered. Zhou et al. emphasized
the importance of the design on the mechanical properties of the final product, fundamen-
tal to mimicking the native breast characteristics [97]. Given the importance of resembling
the natural breast properties, Tytgat et al. focused on the development of soft scaffolds,
using a material extrusion-based 3D printer. Studies confirmed similarities between the
manufactured devices and native tissue. Moreover, scaffolds were able to support ADSCs
differentiation [98]. As previously mentioned, one of the main advantages of the 3DP tech-
nique is its versatility. This advantage was exploited by Dang et al., who combined breast
regeneration with the possibility of simultaneously administering the drug to prevent sur-
gical complications. Indeed, in the proof-of-concept study, they developed by FDM a PCL
scaffold able to guide tissue regeneration. The scaffold was subsequently loaded with
chemotherapeutic drugs (DOX and paclitaxel) and antibiotics (cefazolin) to prevent recur-
rence and infection [99]. In 2017, two start-ups were launched, aiming to provide a valid
alternative to silicone prostheses. LATTICE MEDICAL developed a bioprosthesis, called
MAT(T)ISSE, using the FDM technique. MAT(T)ISSE provides volume to the breast and
allows adipose tissue regeneration. In addition, it degrades in one year, requiring only
one surgery [100]. The company BELLASENO manufactured a PCL resorbable scaffold
that completely degrades in 23 years. The product, called SENELLA BREAST, is de-
signed to be employed for breast reconstruction and augmentation, and it allows fat in-
jection [101].
Figure 6. Showing (a) structure of the scaffold; (bf) implantation of the scaffold and fat injection
process; and (g) scaffold’s properties [94].
Figure 6.
Showing (
a
) structure of the scaffold; (
b
f
) implantation of the scaffold and fat injection
process; and (g) scaffold’s properties [94].
5.3.2. External Prostheses
For breast cancer survivors who have undergone a mastectomy, breast reconstruction
is not always possible; therefore, an external prosthesis can be an alternative for the patient’s
Biosensors 2022,12, 568 14 of 20
wellbeing. Sometimes, however, standard prostheses are not able to meet the requirements
of every individual, resulting in general dissatisfaction. The main problems encountered
are related to failure to appear realistic due to the tactile feel, excessive weight that can
lead to balance and posture issues, and lack of adaptation to the breast anatomy and
natural movements [
102
104
]. To achieve higher satisfaction, increased customization is
necessary [
105
]. The first step in the manufacturing process of prosthetics involves the
scan of the anatomy of the patients, which is essential to obtain accurate information.
From the acquired information, the prosthesis can be designed accordingly and finally
produced either by direct printing or by printing the mold that will be subsequently
filled [
106
]. This strategy was employed by Maillo et al., who developed an external
prosthesis in thermoplastic polyurethane (TPU) and polyvinyl acetate (PVA) using the
FDM technique [
107
]. Alternatively, Unit et al. produced a mold to be filled with silicone,
using the SLS technique [
108
]. Three-dimensional-printed molds can also be a useful
template to help the surgeon to shape the flap that will be employed in the autologous
reconstruction of the breast. This procedure reduces the duration of the surgery and
allows for a better outcome, in particular for the symmetry of the breast [
109
,
110
]. An
interesting study was conducted by Hao et al., who explored the possibility of combining
breast reconstruction and chemotherapy treatment by producing a local implant with
polydimethylsiloxane loaded with paclitaxel and DOX microspheres. For this purpose, the
implant mold was designed and produced by 3DP to confer customizability.
In vivo
studies
conducted on mice suggested that the system could prevent recurrence and metastasis
formation in mice [111].
5.3.3. Nipple–Areola Complex Reconstruction
The last step of breast reconstruction concerns the nipple–areola complex, whose
restoration significantly impacts the overall satisfaction of the patient. At present, the
application of 3DP technology in this area is limited to the production of acellular scaffolds
or bio-printable ink loaded with cells, able to support and guide the natural tissue restora-
tion [
112
,
113
]. Aiming to avoid possible rejection and achieve a long-term nipple projection,
Samadi et al. manufactured a cylinder scaffold made of polylactic acid (PLA) embedded
with autologous tissue from the costal cartilage. Despite the promising results in mice, the
authors found some limitations, mainly related to the degradation time and the rigidity
of the scaffold matrix [
114
]. Therefore, in a later study conducted by the same group, the
PLA was replaced with poly-4-hydroxybutyrate to produce a fully absorbable device [
115
].
Healshape is a start-up founded in Lyon in 2020. They are developing bioprinted prostheses
both for breast augmentation and for nipple–areola complex regeneration. The design
allows cell colonization and tissue regeneration [116].
Although 3DP technology provides numerous advantages in the manufacture of ad-
vanced and complex devices at lower costs, the clinical applications are still limited. Therefore,
further improvements should be achieved to make it moreaccessible in practical employment.
6. Four-Dimensional Printing Applications in Breast Cancer
Despite the promising advantages that 4DP enables, the field is still in its infancy. At
present, the only documented application of 4DP in breast cancer consists of the develop-
ment of scaffolds with NIR-triggered DOX delivery (Figure 7), using extrusion-based 3DP.
In 2020, Wei et al. developed a core–shell scaffold. The incorporation of PDA provides the
responsiveness to NIR irradiation; indeed, under stimulation, the core underwent sol/gel
transition, resulting in drug release. The resulting scaffold could potentially be placed after
breast conservative surgery; moreover, the irradiation provided a photothermal effect that
could prevent recurrence [
117
]. Later, based on the same principle, the research group
produced a drug-loaded alginate–gelatin core scaffold coated with PCL and subsequently
coated with PDA. The presence of PCL enabled a controlled and sustained release of the
drug. Moreover, the scaffold showed wound healing properties [
118
]. NIR-triggered drug
release represents one of the multiple opportunities that 4DP could provide in breast cancer
Biosensors 2022,12, 568 15 of 20
management. Given the benefits of 4DP, especially in the personalization possibilities, other
strategies should be explored. Considering the recent results achieved by shape memory
effect materials, they are expected to provide a valuable contribution in the pharmaceutical
field, including in breast cancer treatment and reconstruction purposes.
Biosensors 2022, 12, x FOR PEER REVIEW 16 of 22
that could prevent recurrence [117]. Later, based on the same principle, the research group
produced a drug-loaded alginategelatin core scaffold coated with PCL and subsequently
coated with PDA. The presence of PCL enabled a controlled and sustained release of the
drug. Moreover, the scaffold showed wound healing properties [118]. NIR-triggered drug
release represents one of the multiple opportunities that 4DP could provide in breast can-
cer management. Given the benefits of 4DP, especially in the personalization possibilities,
other strategies should be explored. Considering the recent results achieved by shape
memory effect materials, they are expected to provide a valuable contribution in the phar-
maceutical field, including in breast cancer treatment and reconstruction purposes.
Figure 7. Schematic illustration of NIR-triggered drug release.
7. Regulatory Considerations
Currently, the major obstacle that limits the application of AM in real-life practice is
the lack of well-defined regulatory guidance. Indeed, 3D-printed products are regulated
under the same pathways as non-additive manufactured devices. They are classified as
Class I, II, or III, depending on the risk of injury for the user and the level of control nec-
essary to guarantee safety and effectiveness [119]. In 2017, the Food and Drug Administra-
tion’s (FDA) Center for Devices and Radiological Health (CDRH) published a guideline
on 3D-printed medical devices and prosthetics. The guideline covers three main aspects:
the design, manufacturing, and tests to be performed. In the Design and Manufacturing
section, technical considerations are included to fulfill the Quality System (QS) require-
ments to ensure product quality and safety. While the Device Testing Considerations sec-
tion provides the information requested for the submission and approval [120]. However,
guidelines can be restrictive and involve a long bureaucratic process. Scaling up to comply
with the Good Manufacturing Practice (GMP) can require high costs. Moreover, meeting
the FDA requirements for clinical trials can be difficult considering the nature of AM,
which is based on individuality [121]. From this, it follows that traditional approaches are
preferred. To take a step toward the implementation of AM in everyday life, collabora-
tions within academia, industry, and FDA are fundamental.
8. Conclusions and Future Perspectives
During the past years, advancements in AM technology and material science, com-
bined with the increasing interest in PM, have prompted new strategies in the biomedical
field. Three-dimensional printing and four-dimensional printing technologies have
shown the potential to revolutionize cancer management by providing a higher level of
personalization. Indeed, tumor heterogeneity restricts the efficacy of standard treatments,
highlighting the urgency for alternative approaches. PM is focused on the impact of
Figure 7. Schematic illustration of NIR-triggered drug release.
7. Regulatory Considerations
Currently, the major obstacle that limits the application of AM in real-life practice is the
lack of well-defined regulatory guidance. Indeed, 3D-printed products are regulated under
the same pathways as non-additive manufactured devices. They are classified as Class
I, II, or III, depending on the risk of injury for the user and the level of control necessary
to guarantee safety and effectiveness [
119
]. In 2017, the Food and Drug Administration’s
(FDA) Center for Devices and Radiological Health (CDRH) published a guideline on 3D-
printed medical devices and prosthetics. The guideline covers three main aspects: the
design, manufacturing, and tests to be performed. In the Design and Manufacturing section,
technical considerations are included to fulfill the Quality System (QS) requirements to
ensure product quality and safety. While the Device Testing Considerations section provides
the information requested for the submission and approval [
120
]. However, guidelines
can be restrictive and involve a long bureaucratic process. Scaling up to comply with
the Good Manufacturing Practice (GMP) can require high costs. Moreover, meeting the
FDA requirements for clinical trials can be difficult considering the nature of AM, which is
based on individuality [
121
]. From this, it follows that traditional approaches are preferred.
To take a step toward the implementation of AM in everyday life, collaborations within
academia, industry, and FDA are fundamental.
8. Conclusions and Future Perspectives
During the past years, advancements in AM technology and material science, com-
bined with the increasing interest in PM, have prompted new strategies in the biomedical
field. Three-dimensional printing and four-dimensional printing technologies have shown
the potential to revolutionize cancer management by providing a higher level of per-
sonalization. Indeed, tumor heterogeneity restricts the efficacy of standard treatments,
highlighting the urgency for alternative approaches. PM is focused on the impact of dif-
ferent factors (such as lifestyle and environmental conditions) on patients’ responses and
clinical outcomes. Based on these differences, tailor-made strategies can be developed.
At present, the main application of AM in breast cancer concerns the development of
drug-loaded implants and scaffolds. Ideally, the devices should provide controlled drug
delivery, assist tissue reconstruction, and resemble natural tissue. However, sometimes the
immediate aesthetical outcome is overshadowed. Considering the high emotional impact
on breast cancer survivors, research should be addressed to provide complete satisfaction
Biosensors 2022,12, 568 16 of 20
to patients, considering both the treatment and aesthetic success. The possibility of therag-
nostic devices should also be explored to confer an additional tool over the tumor control.
Although 4DP has provided a new strategy to achieve a complex and accurate design with
high customizability, research is still in the initial stage. Challenges related to technological
and material aspects require in depth-understanding to achieve significant advancements
and expand the application possibilities. Moreover, understanding the complexity and
dynamism of biological systems is a key requirement. In addition, quality aspects and
regulatory approvals should be further discussed to successfully translate research into
clinical practice. Once the challenges are overcome, AM will provide endless possibilities
and breakthroughs in the fight against burden diseases, including breast cancer.
Author Contributions:
S.M.: writing—original draft, writing—review and editing. L.C.: writing—
review and editing. D.A.L.: project administration, resources, supervision, writing—review and
editing. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
NIH. Breast Cancer. Available online: https://www.cancer.gov/types/breast/hp/breast-prevention-pdq (accessed on 16 June
2022).
2.
World Health Organization. Breast Cancer. Available online: https://www.who.int/news-room/fact-sheets/detail/breast-cancer
(accessed on 15 June 2022).
3.
Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer Statistics for the Year 2020: An
Overview. Int. J. Cancer 2021,149, 778–789. [CrossRef] [PubMed]
4.
Ellsworth, R.E.; Blackburn, H.L.; Shriver, C.D.; Soon-Shiong, P.; Ellsworth, D.L. Molecular Heterogeneity in Breast Cancer: State
of the Science and Implications for Patient Care. Semin. Cell Dev. Biol. 2017,64, 65–72. [CrossRef] [PubMed]
5.
Dong, M.; Cioffi, G.; Wang, J.; Waite, K.A.; Ostrom, Q.T.; Kruchko, C.; Lathia, J.D.; Rubin, J.B.; Berens, M.E.; Connor, J.; et al. Sex
Differences in Cancer Incidence and Survival: A Pan-Cancer Analysis. Cancer Epidemiol. Biomarkers Prev.
2020
,29, 1389–1397.
[CrossRef]
6.
Harbeck, N.; Penault-Llorca, F.; Cortes, J.; Gnant, M.; Houssami, N.; Poortmans, P.; Ruddy, K.; Tsang, J.; Cardoso, F. Breast Cancer.
Nat. Rev. Dis. Primers 2019,5, 66. [CrossRef] [PubMed]
7.
Place, A.E.; Huh, S.J.; Polyak, K. The microenvironment in breast cancer progression: Biology and implications for treatment.
Breast Cancer Res. 2011,13, 227. [CrossRef] [PubMed]
8.
Espina, V.; Liotta, L.A. What is the malignant nature of human ductal carcinoma in situ? Nat. Rev. Cancer
2011
,11, 68–75.
Available online: https://www.nature.com/articles/nrc2950 (accessed on 27 June 2022). [CrossRef] [PubMed]
9.
American Cancer Society. Breast Cancer What Is Breast Cancer? Am. Cancer Soc. Cancer Facts Figure Atlanta Ga Am. Cancer Soc.
2022, 1–19.
10.
Viale, G.; Regan, M.M.; Maiorano, E.; Mastropasqua, M.G.; Dell’Orto, P.; Rasmussen, B.B.; Raffoul, J.; Neven, P.; Orosz, Z.;
Braye, S.; et al. Prognostic and Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors in a
Randomized Trial Comparing Letrozole and Tamoxifen Adjuvant Therapy for Postmenopausal Early Breast Cancer: BIG 1. J.
Clin. Oncol. 2022,25, 3846–3852. [CrossRef]
11.
Nicholson, R.I.; Johnston, S.R. Endocrine Therapy–Current Benefits and Limitations. Breast Cancer Res. Treat.
2005
,93, S3–S10.
[CrossRef]
12. Huang, M.; Wu, J.; Ling, R.; Li, N. Quadruple Negative Breast Cancer. Breast Cancer 2020,27, 527–533. [CrossRef]
13.
Disparity, R.; Determinants, S. Racial Disparity and Triple-Negative Breast Cancer in African-American women: A multifaceted
affair between obesity, biology, and socioeconomic determinants. Cancers 2018,10, 514. [CrossRef]
14.
Minami, C.A.; King, T.A.; Mittendorf, E.A. Patient Preferences for Locoregional Therapy in Early-Stage Breast Cancer. Breast
Cancer Res. Treat. 2020,183, 291–309. [CrossRef] [PubMed]
15.
Breast, E.; Trialists, C.; Group, C. Effect of Radiotherapy after Breast-Conserving Surgery on 10-Year Recurrence and 15-Year
Breast Cancer Death: Meta-Analysis of Individual Patient Data for 10 801 Women in 17 Randomised Trials. Lancet
2011
,378,
1707–1716. [CrossRef]
16.
American Cancer Society. Surgery for Breast Cancer. Available online: https://www.cancer.org/cancer/breast-cancer/treatment/
surgery-for-breast-cancer.html (accessed on 15 June 2022).
17.
American Cancer Society. Radiation for Breast Cancer. Available online: https://www.cancer.org/cancer/breast-cancer/
treatment/radiation-for-breast-cancer.html (accessed on 22 June 2022).
18.
Lee, G.K.; Sheckter, C.C. Breast Reconstruction Following Breast Cancer Treatment-2018. JAMA J. Am. Med. Assoc.
2018
,320,
1277–1278. [CrossRef]
Biosensors 2022,12, 568 17 of 20
19. Gladfelter, J. Breast Augmentation 101. Plast. Surg. Nurs. 2007,27, 136–145. [CrossRef] [PubMed]
20. Maxwell, G.P.; Gabriel, A. Breast Implant Design. Gland Surg. 2017,6, 148–153. [CrossRef] [PubMed]
21.
Shridharani, S.M.; Bellamy, J.L.; Mofid, M.M.; Singh, N.K. Interesting Case Series Breast Augmentation. Eplasty
2013
,13.
Available online: https://www.yumpu.com/en/document/view/28977958/interesting-case-series- breast-augmentation-eplasty
(accessed on 22 June 2022).
22. Spear, S.L.; Mesbahi, A.N. Implant-Based Reconstruction. Clin. Plast. Surgery 2007,34, 63–73. [CrossRef] [PubMed]
23.
Manyam, B.V.; Shah, C.; Woody, N.M.; Reddy, C.A.; Weller, M.A.; Juloori, A.; Naik, M.; Valente, S.; Grobmyer, S.; Durand, P.;
et al. Long-Term Complications and Reconstruction Failures in Previously Radiated Breast Cancer Patients Receiving Salvage
Mastectomy with Autologous Reconstruction or Tissue Expander/Implant-Based Reconstruction. Breast J.
2019
,25, 1071–1078.
[CrossRef]
24.
Visscher, L.E.; Cheng, M.; Chhaya, M.; Hintz, M.L.; Schantz, J.T.; Tran, P.; Ung, O.; Wong, C.; Hutmacher, D.W. Breast Augmenta-
tion and Reconstruction from a Regenerative Medicine Point of View: State of the Art and Future Perspectives. Tissue Eng. Part B
Rev. 2017,23, 281–293. [CrossRef]
25.
Glaus, S.W.; Carlson, G.W. Long-Term Role of External Breast Prostheses After Total Mas