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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_612_Библиотеки_им_академика_М_И_Перельмана
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DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy.
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2020;21(2):387-400.
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fracture repair surgery. J Hand Surg Am. 2017;42(12):1003-1008.
the surgical site for the management of postoperative pain. Cochrane Database Syst Rev.
2017;2:CD011419.
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CHAPTER 12 Concepts of Tissue
Engineering
Sashank Reddy and Salih Colakoglu
KEY POINTS
Tissue engineering is a multidisciplinary field that seeks
to replace or augment bodily structures with
manufactured substitutes.
Tissue-engineered solutions typically combine biomaterial
scaffolds with cell sources and biologic cues needed to
guide their development.
Host interactions with tissue-engineered devices are a
key determinant of durability and functional outcome.
Improvements in manufacturing and tissue integration are
enabling engineered solutions to increasingly
complement grafts and flaps in the plastic surgeon’s tool
kit.
Tissue engineering is a multidisciplinary field that seeks to replace or
augment bodily structures with manufactured substitutes. Although
conventional autologous reconstructions such as grafts and flaps
require harvest of donor tissues, tissue engineering aims to create
new tissues de novo. Unlike conventional prosthetic reconstructions,
tissue-engineered solutions are living biologic entities that aim to
functionally integrate into the body. The basic tripartite schema of
tissue engineering combines cells with biomaterial scaffolds and
provides biologic cues to guide their development into desired
structures (Figure 12.1).1 Even though the first attempts at tissue
engineering date back at least 50 years, the last 2 decades have
seen more rapid progress.2 Improvements in cell sourcing,
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biomaterials design and manufacture, developmental biology, and
immunology have converged to enable more sophisticated tissue
replacements. In this chapter, we review foundational concepts of
tissue engineering, survey clinical applications, and identify
remaining challenges to more widespread clinical adoption.
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FIGURE 12.1. The tripartite schema of tissue
engineering. Cellular building blocks are grown on
supportive and instructive scaffolds and provided with
morphogenic signals to create desired tissues. (From
Almouemen N, Kelly HM, O’Leary C. Tissue engineering:
understanding the role of biomaterials and biophysical
forces on cell functionality through computational and
structural biotechnology analytical methods. Comput
Struct Biotechnol J. 2019;17:591-598 and apated from
Mhanna R, Hasan A. Introduction to tissue engineering. In:
Hasan A, ed. Tissue Engineering for Artifical Organs:
Regenerative Medicine, Smart Diagnostics and
Personalized Medicine. New Jersey, USA: Wiley-VCH;
2017.)
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BIOMATERIALS
The creation of a human ear on the back of an experimental mouse
—published in Plastic and Reconstructive Surgery in 1997—
illustrates the basic strategy tissue engineers use to create new
structures (Figure 12.2).3 Typically, biomaterial scaffolds are
combined with cells and additional physicochemical cues are
provided to drive them toward a desired outcome. The scaffolds
serve several vital functions for tissue-engineered structures. They
provide a physical substrate for cell attachment, enable diffusion of
nutrients and waste products, and in some cases provide instructive
cues for cell differentiation. In native tissues, scaffolds are composed
of proteins and polysaccharides secreted by cells, which together
constitute an extracellular matrix (ECM) that houses cellular
inhabitants. The scaffolds used in tissue engineering are composed
of biomaterials, a specialized class of materials with properties
compatible with cells and tissues. Ideally, such materials support cell
survival, elicit minimal fibrosis or immune reactivity, have physical
properties congruent with the desired tissues, and are easy to
manufacture. A wide range of materials have been used in
reconstruction over decades and new ones emerge regularly.
Several classes of biomaterials, their respective advantages, and
their use cases are reviewed below.
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FIGURE 12.2 Vacanti mouse. This tissue-engineered
auricle comprising bovine chondrocytes cultured on a
polylactic-co-glycolic acid/polylactic acid framework was
published by Joseph Vacanti and colleagues in 1997.
(From Cao Y, Vacanti JP, Paige KT, Upton J, Vacanti CA.
Transplantation of chondrocytes utilizing a polymer-cell
construct to produce tissue-engineered cartilage in the
shape of a human ear. Plast Reconstr Surg.
1997;100(2):297-302.)
Biomaterials can be classified as permanent versus transitory and
synthetic versus biologically derived. Most permanent materials used
in reconstruction are not suitable for tissue engineering applications
as they do not integrate well with cells. Such materials like steel,
titanium, and silicone are therefore mainly used in inert prosthetics
rather than in living tissue-engineered constructs. Some examples of
permanent biomaterials that are used for tissue engineering include
calcium phosphates used in bone regeneration and polyester grafts
used in vascular repair. Some synthetic permanent biomaterials such
as calcium hydroxyapatite and beta-tricalcium phosphate have been
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used along with inductive factors and osteogenic cells to fill critical
bone defects in clinical studies.4 Demineralized bone matrices are
another example of permanent biomaterials used in tissue
engineering. These can be placed into bone defects where their
osteoconductive properties enable migration of osteogenic
precursors from the surrounding bone up to a distance of several
hundred micrometers.5 Demineralized bone matrix can also be
combined with patient- derived cells from morselized bone generated
intraoperatively during reconstruction. Polymethyl methacrylate
(PMMA) is a synthetic semipermanent polymer that lacks
osteoinductive qualities on its own but has mechanical properties
suitable for bone repair applications. In particular, the high resistance
of PMMA to compressive and torsional forces makes it useful as a
bone cement. When combined with osteoinductive agents such as
bone morphogenetic protein 2 (BMP-2), PMMA-based scaffolds can
result in creation of new bone in experimental applications.6 In
vascular repair, polyester grafts such as Dacron and Gore-Tex have
been coated with fibronectin or other adhesion-promoting materials,
and then seeded with endothelial cells prior to implantation, yielding
biosynthetic conduits with patency rates comparable to primary vein
grafts.
7,8
The placement of unseeded polyester grafts however does
not lead to durable endothelial migration. Unseeded, uncoated
vascular grafts in human studies rarely exceed 1 cm of endothelial
ingrowth from the site of anastomosis.
9
In contrast to these permanent biomaterials, biodegradable,
nonpermanent substrates have enjoyed wide use in tissue
engineering, with applications in skin and soft-tissue restoration,
fascial repair, nerve repair, vascular repair, and even functional
organ restoration of heart and lungs in preclinical models. These
transitory biomaterials are meant to support cell survival and host
tissue integration in the postimplantation period, but over time, they
are degraded and replaced with ECM created by embedded and
host cells.
Selection of biodegradable polymers can be optimized across
several parameters—mechanical properties, degradation time, and
ease of functionalization—depending on the biological application.
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Mechanical properties of the biomaterial scaffold should closely
mimic those of the tissue to be reconstructed. Relevant parameters
include strength (the capacity to withstand compressive and tensile
forces without breaking), elasticity (the capacity to return to the
original state after stretching), and stiffness (resistance to
deformation with applied stress). These interrelated factors govern
not only the physical properties of tissue-engineered constructs but
also their interaction with embedded and host cells. In their seminal
2006 study, Discher and colleagues reported that substrate elasticity
biases the differentiation of multipotent stem cells—with
comparatively softer substrates promoting myogenic differentiation
and stiffer substrates leading to osteogenic differentiation.
10
Degradation time is also a critical parameter influencing biomaterial
choice with most used biodegradable materials resorbing on a
timescale of months to years. The materials must have sufficient
durability to enable replacement by ECM created by embedded and
host cells—a factor that varies depending on the tissue being
created.
Biodegradable biomaterials can be further classified as synthetic
or biologically derived. The most common synthetic forms comprise
polymers—repeating units of chemical or biologic building blocks. A
major class of biodegradable polymers are polyesters such as
polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone
(PCL), and polylactic-co-glycolic acid (PLGA). Several of these have
been used in Food and Drug Administration (FDA)–approved
medical devices, making them particularly attractive for tissue
engineering applications.11 These polymers have a wide range of in
vivo degradation times—from months to years—enabling
optimization across a range of tissue engineering applications. Other
synthetic polymers used in tissue engineering include hydrogels—
soft, cross-linked hygroscopic materials that are well suited to
carrying cells. The most widely used synthetic hydrogel is
polyethylene glycol and its derivatives such as polyethylene glycol
diacrylate. Another hydrogel, polyvinyl alcohol (PVA), has been used
in three-dimensional (3D) printing and cartilage engineering
applications.12 In addition to their use as standalone agents, these
various polymers can be blended to achieve ideal performance. For
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example, PCL-PLA blends have been used to create highly porous,
elastic biomaterial scaffolds capable of supporting cell attachment
and proliferation.
13
In addition to these synthetic polymers, a wide variety of
biologically derived polymers are suitable for scaffold creation.
These include collagen, elastin, hyaluronic acid (HA), fibrin, alginate,
and silk. Collagens constitute the major proteinaceous component of
human ECM and account for nearly one third of all body protein in
aggregate. In natural tissues, collagen polymer units known as
tropocollagen form a triple helical substructure that undergoes
chemical cross-linking into larger units of fibrils and ultimately fibers.
Given their broad deployment in native tissues and organs,
collagens are a natural choice as biomaterials for tissue engineering.
Collagen used in tissue engineering can be obtained from porcine,
bovine, and avian (rooster comb), as well as cadaveric and
recombinant sources. A subset of patients develop hypersensitivity
reactions to animal- derived collagens as was noted with the original
collagen-based dermal fillers such as Zyderm.14 Therefore, the
clinical development of fully human recombinant collagens such as
those developed by CollPlant15 is eagerly anticipated. While a broad
range of mechanical properties and good biocompatibility
recommend collagen as a biomaterial, its rapid rate of degradation in
unmodified form limits its applications as a standalone scaffolding
material. As a dermal filler, for example, the collagen-based Zyderm
enabled only a few months of volume restoration.14 Fortunately,
chemical cross-linking of collagen proteins can overcome this issue
while further enhancing mechanical properties.
16
Like collagen, elastin is another natural biopolymer component of
ECM that has been co-opted by tissue engineers. In native tissues,
tropoelastin monomers are cross-linked to form elastin fibers. As the
name might suggest, elastin fibers have a high elastic modulus,
allowing them to resist deformational forces created by embedded or
host cells.17 Nonetheless, the modest mechanical strength of elastin
polymers often necessitates augmentation with synthetic
biomaterials such as PCL and PLGA and has relegated such
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