Additive Manufacturing of Biomaterials, Tissues, and Organs

doi:10.1007/S10439-016-1719-Y

Editorial

()

Abstract—The introduction of additive manufacturing

(AM), often referred to as three-dimensional (3D) printing,

has initiated what some believe to be a manufacturing

revolution, and has expedited the development of the ﬁel d

of biofabrication. Moreover, recent advances in AM have

facilitated further development of patient-speciﬁc health-

care solutions. Customization of many healthcare products

and services, such as implants, drug delivery devices,

medical instruments, prosthetics, and in vitro models, would

have been extremely challenging—if not impossible—with-

out AM technologies. The current special issue of the

Annals of Biomedical Engineering pres ents the latest trend s

in application of AM techniques to healthcare-related areas

of research. As a prelude to this special issue, we review here

the most important areas of biomedical research and clinical

practice that have beneﬁted from recent developments in

additive manufacturing techniques. This editorial, there-

fore, aims to sketch the research landscape within which the

other contributions of the special issue can be better

understood and positioned. In what follows, we brieﬂy

review the application of additive manufacturing techniques

in studies addressing biomaterials, (re)generation of tissues

and organs, disease models, drug delivery systems, implants,

medical instruments, prosthetics, orthotics, and AM objects

used for medical visualization and communication.

Keywords—Bioprinting, Biofabrication, Biomaterials, Drug

delivery, Medical devices, Tissue regeneration.

INTRODUCTION

Additive manufacturing (AM), also known as 3D

printing, has emerged during recent years as a ﬂexible

and powerful technique for advanced manufacturing in

healthcare. Even though the underlying technology has

been in development for more than two decades, the

level of maturity and perfection required for real-world

applications has been achieved only recently. Most

importantly, a wide range of biomedical materials can

now be processed using additive manufacturing tech-

niques with increasing accuracy. Moreover, a number of

AM processes and the resulting products have already

been approved by regulatory bodies for (routine) clini-

cal use, and a draft ver-

sion of FDA guidance for

additively manufactured

devices has already been

published.

1

At the same

time, AM technology has

been applied for (re)gen-

eration of living tissue

structures that could be

applied as regenerative

implants and disease

models. This ﬁeld of

‘‘biofabrication’’

28

is

developing exponentially,

underscoring the poten-

tial of applying AM in

healthcare. Some other

areas, such as pharma-

cology, oncology, sur-

gery, and rehabilitation

have also provided inter-

esting clinical and research

applications for additive

manufacturing.

The current special is-

sue aims to review and

showcase some of the

most promising trends in

application of AM to

healthcare. This review

and the research articles

presented here cover a wide range of applications, rang-

ing from cardiovascular

19

to orthopedic,

9,10,58

craniofa-

cial,

50

and drug screening.

71

As a prelude to this special

issue, we decided to write an extended editorial and

brieﬂy review the most important trends in application of

AM to healthcare, thereby setting the stage for what

appears in the rest of the issue. In that sense, this editorial

might be seen as a ‘‘review of reviews,’’ where we do not

try to engage in the details of various areas of research

but rather to sketch the bigger picture through clear

examples, reference to the papers appearing in this special

Amir A. Zadpoor

Jos Malda

1

Food and Drug Administration (FDA), Technical Considerations

for Additive Manufactured Devices—Draft Guidance for Industry

and Food and Drug Administration Staff, Issued on May 10, 2016.

Annals of Biomedical Engineering, Vol. 45, No. 1, January 2017 (Ó 2016) pp. 1–11

DOI: 10.1007/s10439-016-1719-y

0090-6964/17/0100-0001/0 Ó 2016 Biomedical Engineering Society

1

issue, as well as to the other essential literature. In par-

ticular, we have not tried to review the details of AM

techniques (

Fig. 1), as these can be found in some of the

excellent review papers appearing in this issue; see, e.g.,

Refs.

32, 48, 53, 79. Instead, the areas where AM could

improve the quality of healthcare are reviewed in the

following sections of this editorial, which are organized in

order of perceived impact.

ADDITIVE MANUFACTURING

OF BIOMATERIALS

The form freedom oﬀered by AM techniques pro-

vides many opportunities for fabrication of bio mate-

rial constructs with complex and precisely controlled

external and internal shape. Although the external or

macroscale shape of biomaterial structures is impor-

tant, AM oﬀers the additional opportunity to also

control the internal shape or microarchitecture of the

generated structures (Fig. 2), which may positively

inﬂuence tissue regeneration and integratio n. More-

over, the internal microarchitecture will affect the

physical, mechanical, and biological properties of

porous biomaterials;

75

For example, the static

mechanical properties,

2,8,60

fatigue behavior,

4

and

permeability

69

of porous biomaterials have been shown

to be functions of their geometrical parameters. Other

geometrical features such as the sign and intensity of

curvature have been shown to regulate the rate of tis-

sue regeneration.

22,57,75

AM techniques make it possi-

ble to use almost any design of microarchitecture to

achieve a desired set of physical, mechanical, and

biological properties. Furthermore, full interconnec-

tivity in the porous space of biomaterials can be

achieved. By ration ally designing the microarchitec-

ture, unusual mechani cal properties, such as negative

Poisson’s ratio or independently varying, i.e., decou-

pled, porosity and mechanical properties, can be

achieved as well.

76

Such rational design of biomaterial

microarchitecture is something that ﬁts within the

larger context of mechanical metamaterials and has

received increasing attention recently.

73

Furthermore,

the microarchitecture of biodegradable biomaterials

inﬂuences their degradation proﬁle and the resulting

tissue regeneration performance of (highly) porous

biomaterials.

13,14,78

Rational design of microarchitec-

ture and subsequent AM could, therefore, also be used

for adjustment of the biodegradation proﬁle of bio-

materials.

Various categories of AM techniques (Fig. 1) have

been used for processing a wide range of polymeric,

metallic, and ceramic biomaterials. As far as polymeric

materials are concerned, AM techniques based on vat

polymerization, such as stereolithography (SLA),

those based on material extrusion techniques such as

fused deposition modeling (FDM), those based on

powder bed fusion technologies such as selective laser

sintering (SLS), and material jetting alternatives, such

as inkjet printing, are commonly used (Fig.

1). The

most widely used techniques for processing metallic

biomaterials are currently based on powder bed fusion,

such as selective laser melting (SLM) and electron

beam melting (EBM) (Fig.

2). A large number of

studies using AM techniques for processing of ceramic-

based biomaterials applied binder jetting, material

extrusion, powder bed fusion, or vat polymeriza-

tion.

1,64

However, indirect AM

32

is another, particu-

larly interesting approach, where biomaterials are not

made through direct AM but are fabricated through a

medium that is additively manufactured; For example,

the negative of an intended biomaterial structure may

be additively manufactured to allow for casting of the

desired biomaterial. Direct and indirect methods can

also be combined to enable fabrication of more com-

plex biomaterial components.

There are two major challenges that need to be

addresse d to utilize th e maximum poten tial of AM

techniques for improving the performance of bioma-

terials. First, the optimal microarchitecture for the

performance of each biomaterial is often unclear.

Analytical and multiphys ics computational modeling

techniques need to be used to determine the best

microarchitecture for any speciﬁ c application. Ideally,

all relevant mecha nical, physical, and biological

properties of the biomaterial should be considered

simultaneously when designing the microarchitecture.

Secondly, there is still limited availability of materi als

that are c ompatible with AM processes. Traditionally

used biomaterials can often not be pro cessed with AM

techniques, whilst the best-performing materials in

AM machines, in terms of accuracy and functionality,

are not biocompatible or do not exhibit the required

biodegradation be havior. It is, therefore, essential not

only to improve the arsenal of available biomaterials,

but also to adapt current AM technologies to better

process the best available biomaterials . In vi ew of this,

developments in both AM materials and systems is

required to utilize the potential of AM to its full ex-

tent.

TISSUE AND ORGAN EQUIVALENTS

Biofabrication encompasses the automated genera-

tion of tissue constructs by means of bioprinting,

bioassembly, and subsequent maturation. As such, it

oﬀers the opportunity to generate constructs that more

closely match the composition and structure of native

tissues. An important diﬀerence between biofabrica-

A. A. ZADPOOR AND J. MALDA2

tion (Fig. 3) and other types of AM is the incorpora-

tion of cells in the printed biomaterial,

41,44,59

which

together with the cells is refer red to as bioink. The

most widely applied AM techniques for bioprinting

with bioinks are based on laser-induced forward

transfer (LiFT), inkjet printing, and robotic dispens-

ing.

41

The advantages, disadvantages, and limitations

of each of these techniques are further reviewed in a

number of contributions to this special issue.

19,39,53,71

The printed combinat ion of biomaterials, biomole-

cules, and cells is supposed to gradually mature into

the desired tissue. The incorporated biomaterial ideally

provides the required initial mechanical support,

structural support for mass and gas transfer, and

physical cues for activating the appropriate mechan-

otransductory pathways. At the same time, the bio-

molecules incorporated into the bioink provide the

required biological cues to guide the tissue regenera-

tion process. Multi ple bioinks and cell types can be

distributed within the same tissue construct to best

guide the tissue generation process and to enable

regeneration of more complex tissue structures. Ad-

vanced imaging can assist with quantiﬁcation of the

shape of defects in the tissue/organ and potentially also

its speciﬁc composition. The acquired images could be

further processed to obtain a computer-aided design

(CAD) ﬁle describing the exact geometry of the desired

patient-speciﬁc tissue/organ construct. The patient-

speciﬁc aspect is further underscored by the potential

to use autologous cell sources, minimizing the chance

of rejection of the generated tissue/organ. Biofabrica-

tion is currently being explored as an approach for

generation of various types of tissue constructs,

including cartilage,

58

bone,

39

skin,

39

periodontal tis-

sues,

12

different types of vascularized tis sues,

56

and

cardiovascular tissues.

19

In addition to generating tis-

sue constructs for replacement or repair of damaged

tissues, bioprinted tissues could also be used in vitro as

tissue analogies in toxicity and disease models

72

or for

(patient-speciﬁc) drug screening,

71

potentially

decreasing the need for anima l experiments.

Nevertheless, it still remains a challenge to ensure

that the generated bioprinted tissue structures properly

match the structure and properties of the native tissue.

FIGURE 1. Different categories of additive manufacturing technologies according to the terminology proposed by ISO/

ASTM52900:2015.

Additive Manufacturing of Biomaterials, Tissues, and Organs 3

A current limitation is the limited availability of

bioinks that possess appropriate physical properties

for the printing process and simultaneously provide a

suitable niche for the cells to diﬀerentiate towards the

desired lineage. Diﬀerent classes of hydrogels have

been employed as parts of bioink systems used in tis-

sue/organ bioprinting.

41,43,45,55,62

A promising approach to simultaneously comply

with the numerous requirements that AM techniques

and bioinks must satisfy to guarantee optimal tissue

quality and maximum tissue co mplexity is to combine

various AM technologies and bioinks to beneﬁt from

the best aspects of diﬀerent approaches. Recent

application of this pragmatic approach has produced

some promising results.

36

DRUGS AND DRUG DELIVERY

Various techniques for drug administration and

delivery devices including solid dosage forms,

26

implantable drug delivery vehicles,

23,33

and topical

drug delivery systems

25

could beneﬁt from what AM

has to offer. The recent approval of an AM drug

product by the FDA in August 2015

49

marked the

beginning of an era where more additively manufac-

tured drugs are expected to enter routine clinical use.

In traditional dru g delivery research, the main focus is

on controlling the release proﬁle through various

approaches, among which the most important is

development of new biomaterials with distinct, con-

trollable, and predictable release proﬁles. AM offers an

alternative approach for development of new drug

delivery systems with tailorable release proﬁles by

adjusting the 3 D shape

26

and microarchitecture of the

drug delivery system, as well as by varying the spatial

distribution of active agents

27

(Fig. 4). Moreover,

multiple drugs could be integrated into a single drug

delivery system with the possibility of precisely con-

trolling the release proﬁles of individual drugs (Fig.

4).

Furthermore, AM allows for on-demand manufactur-

ing of drug delivery systems,

49

which is particularly

useful for unstable drugs with limited shelf life.

49

The

shape and dose could also be adjusted relatively easily.

AM techniques based on binder jetting, material

extrusion,

18

and material jetting could be used for

fabrication of drug delivery systems

49

(Fig. 1). Among

the different categories of drug delivery systems, solid

dosage forms have received the most attention given

their relatively easy route to clinical use and huge

potential for commercialization. The effects of the

above-mentioned design parameters on the release

proﬁles of drug delivery systems in general and solid

dosage forms in particular have not yet been fully

understood and require further research.

Computational modeling can aid prediction of re-

lease proﬁles from various drug delivery systems

6,31,40

and may be of particular value for drug delivery sys-

tems based on AM structures. These computational

models will provide insights into the effects of the

geometrical design, microarchitecture, and spatial dis-

tributions of active and passive agents on the release

proﬁles. The combination of AM techniques and

computational models for achieving desired release

proﬁles is a relatively unexplored area of research and

is suggested to be an important area for future

research.

IMPLANTS

AM has added a new dimension to the design and

manufacturing of implants in general, and patient-

speciﬁc implants in particular. Patient-speciﬁc

implants,

24,46,47

where the implant is designed to ﬁt the

anatomy or other requirements of a single patient, are

one of the prime areas for routine clinical application

of AM techniques. Recent advances close the loop in

the pipeline that goes from image acquisition to image

processing, implant design, and implant manufactur-

FIGURE 2. Additively manufactured porous titanium in the

shape of cylinders (a) and the femur (b) fabricated using

selective laser melting from Ti-6Al-4V at the Additive Manu-

facturing Laboratory, TU Delft (Medical Delta

Ó de Beel-

dredacteur).

A. A. ZADPOOR AND J. MALDA4

ing, as the entire process can now be streamlined

through CAD systems that integrate some or all of the

required steps. The free-form nature of AM process es

enables implants with anatomically complex geome-

tries to be manufactured quickly, reliably, and cost-

effectively. Companies that integrate the various

aspects required for patient-speciﬁc AM are already

active in the market, and their implants are already

used in the clinic.

In addition to enabling pro duction of patient-

speciﬁc implants, AM allows for incorporation of

complex geometrical features not only in patient-

speciﬁc implants but also in generic implants; For

example, additively manufactured implants could

incorporate rationally designed lattice structures into

their design (Fig.

5) to adjust the mechanical proper-

ties of the implants, thereby preventing the stress-

shielding phenomenon. Moreover, the large pore

spaces provided by these lattice structures facilitate

tissue ingrowth and osseointegration. These structures

also provide pore spaces, which could be used for drug

delivery purposes, e.g., to facilitate tissue regeneration

or combat infection.

70

Finally, lattice structures have

huge adjustable surface areas that could be biofunc-

tionalized

68

to achieve improved tissue regeneration

performance

3,17

and antibacterial behavior.

5,67

Ultimately, the de sign of hybrid implants co uld

integrate solid volumes with various types of lattice

structure (Fig.

5). This allows for optimal distribution

of mechanical properties within the implant, providing

sufﬁcient mechanical support in areas where mechan-

ical stress is greatest but allowing for incorporation of

porous structures in areas where stresses are lower,

tissue unloading should be avoided, or bone ingrowth

is essential, such as the surface of the anchoring parts

of the implant. Functionally graded geometries (Fig.

6)

could also be realized using AM techniques such that,

for example, the porosity of the lattice structure

gradually decreases from the implant surface, which is

in contact with tissue and could beneﬁt from tissue

ingrowth, to the center of the implant, which may need

to be stronger to carry mechanical loads.

Metals are the materials most commonly used for

AM of functional and load-bearing implants. Powder

bed fusion processes including selective laser melting

(SLM) and electron beam melting (EBM) are often

used for this purpose.

Streamlined design and digital manufacturing of

patient-speciﬁc implants and incorporation of complex

geometrical features into the design of generic im-

plants, as well as evaluation of the actual clinical per-

formance of patient-speciﬁc implants and implants

incorporating features such as hybrid design and

FIGURE 3. Biofabricated auricular implant: (a) macroscopic appearance of a ﬁber-reinforced biofabricated auricular construct

based on gelatin methacryloyl hydrogel and polycaprolactone ﬁbers, (b) magniﬁed view of reinforcing ﬁbers (white) in the

hydrogel (red), (c) Safranin O staining (stains proteoglycans red) of a histological section of a gelatin methacryloyl hydrogel

construct after 6 weeks in vivo (subcutaneous mouse model) (Utrecht Biofabrication Facility, courtesy of Iris Otto, University

Medical Center Utrecht).

FIGURE 4. Additive manufacturing techniques could be

used to (1) achieve complex distribution of several compo-

nents in solid dosage forms, (2) develop drug products for

speciﬁc patient groups, e.g., children, and (3) adjust the do-

sage of drug products.

Additive Manufacturing of Biomaterials, Tissues, and Organs 5

Additive Manufacturing of Biomaterials, Tissues, and Organs

Citations

References

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