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Translational Challenges: Lymph
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Node Tissue Engineering
PhilippNeßbach andMatthiasM.Aitzetmüller
25
25.1 Introduction
Chronic lymphedema results from a progressive
pathological condition of the lymphatic system.
It is a combination of an accumulation of proteinrich uid, inammation, brosis, and hypertrophy of adipose tissue. This often leads to a clinical
picture of disgurement and decreased mobility
and function. The dysfunction of lymphatic
transport can be described as a lack of removal of
net uid efux from the capillaries. An accumulation in the interstitium and following pressure
on the skin is the result. This interstitial uid is
up to 90% reabsorbed by venous capillaries. In
healthy patients, the remaining 10% are removed
by lymphatic vessels to blood as lymph [1].
Macromolecules like proteins are rst degraded
by macrophages and normally afterwards also
P. Neßbach (*)
Department for Plastic and Hand Surgery,
Klinkum rechts der Isar, Technical University of
Munich, Munich, Germany
e-mail: philipp.nessbach@tum.de
M. M. Aitzetmüller
Department of Plastic and Hand Surgery,
Klinikum rechts der Isar, Technical University of
Munich, Munich, Germany
Section of Plastic and Reconstructive Surgery,
Department of Trauma, Hand and Reconstructive
Surgery, Westfaelische Wilhelms, University of
Muenster, Muenster, Germany
e-mail: aitzetmueller@tum.de
removed by lymphatic vessels from the interstitium [2]. Chronic lymphedema results from an
imbalance in lymph transport.
Lymphedema is classied into primary and secondary causes. Among primary, all congenital
causes are summarized. Furthermore, secondary
lymphedema comprises all causes which are
acquired by disruption of lymph transport.
Congenital hereditary lymphedema as well as
Milroy disease occur in the rst 2 years of life.
Milroy disease is an autosomal-dominant pattern
which mostly affects lower extremities and causes
intestinal lymphangiectasia and cholestasis [3]. It is
known to be connected genetically to a mutation in
the VEGFR-3 tyrosine kinase signaling pathway
[4, 5]. Familial lymphedema praecox, also known
as Meige disease, occurs during puberty. Another
autosomal-dominant pattern which is associated
with the loss of hearing, cerebrovascular malformations, vertebral defects, and distichiasis [6].
Lymphedema tarda is the primary form which
occurs latest in life, that is, after the age of 35 [1].
The most prominent etiology of secondary
lymphedema is lariasis secondary which is caused
by a nematode Wuchereria bancrofti and affects
more than 90 million people worldwide [7]. In
industrial countries, female breast cancer and its
treatment play an important role in the development of chronic lymphedema. According to the
American Cancer Society, there are two million
breast cancer survivors of which 20% suffer from
chronic lymphedema [8]. In Germany there are
© Springer Nature Switzerland AG 2019
D. Duscher, M. A. Shiffman (eds.), Regenerative Medicine and Plastic Surgery,
https://doi.org/10.1007/978-3-030-19958-6_25
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approximately 1.2 million patients suffering from
lymphedema [9]. Mostly upper extremities are
affected by lymphedema with rates from 24% to
49% after mastectomy [10–14] and 4–28% after
lumpectomy [15, 16]. Both main treatments for
breast cancer patients, radiation and dissection of
lymph nodes in the axillary region, increase the risk
of chronic lymphedema [15, 17–20]. After introducing sentinel lymph node biopsy to detect breast
cancer spread, a signicant decrease in lymphedema cases had been shown in comparison to the
traditional dissection of lymph nodes [21–25].
Various known factors such as obesity, infection,
and trauma increase the risk of lymphedema for
women after breast cancer therapy [11, 16, 26, 27].
25.2 Clinical Presentation
andDiagnosis
Lymphedema is characterized by an accumulation of subcutaneous interstitial uid and adipose
tissue. Inammation occurs simultaneously with
the accumulation of uid and the decreased
removal of lymph uid. This also leads to more
fat deposition and lipogenesis which results in an
increased activation of brosis and proliferation
of connective tissue [28–30]. Subcutaneous tissue in patients becomes harder and brosis develops. Furthermore, hypertrophy of adipose tissue
occurs. This rst results in a swelling of the diseased site and is often characterized as brotic
and soft, and turns into a hardened state over
time. The International Society of Lymphology
dened the clinical classication for lymphedema using the following terminology [31]:
• Stage I: Represents an early accumulation of
uid relatively high in protein content (e.g., in
comparison with “venous” edema) and subsides with limb elevation.
• Stage II: Signies that limb elevation no lon-
ger reduces tissue swelling, and pitting is
manifest. Later in Stage II, pitting is less evident as tissue brosis supervenes.
• Stage III: Encompasses lymphostatic elephan-
tiasis where pitting is absent and trophic skin
changes such as acanthosis, fat deposits, and
warty overgrowths occur.
Even though a swelling by itself does not
induce serious symptoms, cellulitis may occur due
to proliferation of microbes in the accumulated
interstitial uid. A common effect is the progression of lymphedema by lymphangitis, which
results in lymphatic vessels destruction.
Papillomatosis, hyperkeratosis, and skin breakdown are additional changes in skin quality that
regularly occur [32]. Lymphangiosarcoma, Kaposi
sarcoma, and lymphoma represent cutaneous
malignant tumors which are rare complications of
chronic lymphedema [33]. A subsection of women
who developed a signicant lymphedema following radical mastectomy and who were diagnosed
with ensuing lymphangiosarcoma are suffering
from Stewart Treves syndrome. Around 200
patients are reported up to now with a mean survival time of 19months [
34–38].
Patient history and clinical presentation are
the basis for diagnosis of lymphedema in later
stages (Table25.1).
Common causes of limb edema are challenging
to differentiate from early stages of lymphedema.
Cardiac failure, protein-losing conditions, local etiologies including lipedema, vein thrombosis, myxedema, chronic venous insufciency, and idiopathic
edema are systemic causes for differential diagno-
Table 25.1 Symptoms and factors for lymphedema
diagnosis
Associated symptoms
Chronic skin breakdown
Recurrent cellulitis
Clinical signs
Soft, pitting edema (early stage)
Cellulitis
Fibrosis and induration (late stage)
Hyperkeratosis
Papillomatosis
Peau d’orange skin changes
Positive Stemmer sign (lower extremity lymphedema)
Reported risk factors
Familial history of congenital lymphedema
History of infection
History of malignancy
History of radiation therapy
History of trauma
Obesity
Prior surgical procedures, particularly nodal dissection
Travel to geographical region with endemic lariasis
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295
sis of lymphedema [1]. Positive Stemmer sign as
well as peau d’orange changes in the skin and cutaneous and subcutaneous brosis are indicators for
lymphedema during physical examination [39, 40].
Circumferential and volumetric measurements are
commonly used for lymphedema documentation
as well as comparison between a patient’s healthy
and diseased limbs. Tonometry, perometry, and
bioelectric impedance analysis are noninvasive,
advanced methods for clinical examination [41–
44]. Analysis in body composition typically make
use of bioimpedance. This technology allows a
direct measurement and is able to differentiate
between edema and limb volume [45, 46].
Bioelectric impedance is a reliable and reproducible technique which has shown the capacity to
indicate lymphedema in women following breast
cancer treatment [47–49].
Magnetic resonance imaging, computed tomography, and lymphoscintigraphy are used if clinical
examination is not capable of a secure diagnosis.
Lymphoscintigraphy makes use of a radiolabeled
marker which is intradermally injected and stains
lymphatic vessels [50, 51]. Delayed transport of
the radiolabeled marker, backow, dermal diffusion, and meager visualization of lymph nodes and
vessels are common anomalies for lymphedema
[52]. Furthermore, computed tomography is a
100% specic and 97% sensitive technique to conrm lymphedema diagnosis [53]. Magnetic resonance imaging is more cost intensive but able to
show a more detailed lymphatic structure. In addition it was shown to have similar sensitivity and
specicity for lymphedema diagnosis, without
exposure to radiation [54].
Radiologic examination techniques for lymphedema diagnosis are only necessary in cases in
which patient history and physical examination
are insufcient. For most patients, there is no need
for lymphoscintigraphy, magnetic resonance
imaging, or computed tomography, and clinical
diagnosis guides the treatment algorithm.
25.3 Traditional Treatment
The most prevalent conservative treatment is
complete decongestive therapy (CDT), which
has become internationally recognized. More
than 90% of lymphedema patients are treated
with CDT.This therapy is supported by its four
mainstays: manual lymphatic drainage, compression treatment, exercise, and skin care. It
needs to be provided by specialized physiotherapists. In addition, CDT is a symptomatic treatment, which makes it necessary to perform CDT
lifelong. The biggest disadvantages are the lack
of disease elimination and the high expenditure
of time. The use of special compression devices
that mimic manual lymphatic drainage is rare.
Due to the danger of centralized edema, this procedure is effective only in a small proportion of
patients and must be supervised by physicians
[55].
Since several decades various surgical procedures have existed; however, none has been
established as a gold standard for lymphedema
treatment. For a small group of patients, who are
suffering from a special combination of lymphedema and lipedema, liposuction offers a longterm symptomatic improvement. However, tissue
removal is a very stressful procedure, which is
rarely performed today [56].
The goal of reconstructive surgery is to correct the cause of the disease by restoring lymphatic drainage. Reconstructive procedures are
only offered in a very few specialized hospitals.
Established operating procedures are bypasses
between lymphatic vessels (lymphatic grafting)
and connections between lymphatic vessels and
veins (lymphovenous anastomosis). Both procedures use elaborate microsurgery with relatively high treatment risks and long surgical
times [57–59]. Alternatively, an autologous
transplantation of lymph nodes (microvascular
lymph node transplantation), lymph node bundle with surrounding fatty tissue, in the sense of
a free ap, is taken from a healthy site and
microsurgically transplanted into the diseased
site. Thereby blood vessels are connected to
each other by complex microsurgery, resulting
in higher risks for the patient and frequent
problems at the donor site, such as secondary
lymphedema. Among the existing surgical procedures, microvascular lymph node transplantation is the most promising [60–63]. A
graphical overview of treatment options is provided in Fig.25.1.
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P. Neßbach and M. M. Aitzetmüller
Fig. 25.1 Traditional and regenerative treatments for chronic lymphedema
25.4 Regenerative Treatment:
Lymph Node Tissue
Engineering
Tissue engineering and its area of clinical application, regenerative medicine, aim to regenerate
the body’s own tissue and organs by introducing
the use of three-dimensional scaffolds, different
cell types, and growth factors. The scaffold serves
as temporary three-dimensional support structure
for mechanical stabilization, organization, proliferation, and differentiation of the involved cells.
Scaffolds take over the function of the extracellular matrix and are subject to correspondingly
high demands. An ideal scaffold should have an
interconnecting pore structure that allows the
migration of cells and their supply of nutrients
and oxygen [64, 65]. These properties were previously difcult to implement by using conventional fabrication methods for scaffolds. In
traditional techniques (textile technologies, plas-
tic processing), the results are not reproducible
(pore size, mechanical properties, lament thickness), or cytotoxic or carcinogenic solvents are
used. These residues have a negative inuence on
the biocompatibility of the scaffold. Through the
introduction of additive manufacturing techniques in tissue engineering, many obstacles
were overcome. The mechanical properties of the
scaffolds could thus be controlled down to small
levels and play an important role in the eld of
tissue engineering and especially in lymph node
regeneration [66, 67]. A suitable scaffold should
have the same biomechanical properties as the
surrounding tissue at the time point of implantation. The degradation of the biodegradable
polymer must fulll requirements such as maintaining rigidity and the three-dimensional structure as well as allowing surrounding cells to
migrate and proliferate [64, 66].
The high potential for regeneration of lym-
phatic tissue is characterized by numerous studies
25 Translational Challenges: Lymph Node Tissue Engineering
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297
by Jaffe etal. and known since the 1920s [68]. In
a rat model, they were able to show, that autologous transplanted lymph nodes regenerate within
6 days. These lymph nodes were previously
transplanted avascular into muscular abdominal
wall. Several years later, in the 1980s and 1990s
the group Papst etal. introduced the concept of
transplanting autologous lymph node fragments
[69–71]. Lymph node fragments were transplanted in different anatomical regions (inguinal,
mesentery of ileum, and omentum majus) of
minipigs. Inguinal transplanted fragments
showed good regeneration, whereas the omentum
majus fragments did not show regenerative characteristics. The group Papst etal. [69] assumed
that subcutaneously transplanted lymph node
fragments are more capable of connecting to
afferent lymphatic vessels than the fragments of
omentum majus.
After several decades and with increasing
progress in regenerative medicine, approaches of
articial lymph nodes were introduced [72]. The
complex three-dimensional structure with cortex
and the composition of various cell types is a big
challenge for researchers [73]. First articial
lymph nodes were made using collagen sponges
and stroma and dendritic cells [74]. These articial lymph nodes were transplanted subcapsular
into kidneys of immunodecient mice. A secondary immune response was shown, starting
from the articial lymph node after antigen
exposure. B and T cells migrated from the articial lymph nodes to the spleen and bone marrow
and became antibody-secreting plasma cells [74,
75]. Another approach is using polyurethane
scaffold which is seeded with murine T zone
broblastic reticular cells. A connection was discovered between interstitial ow velocity and
the secretion of CCL21. At low ow rates, gene
expression of CCL21 was downregulated [76].
CCL21/CCL19 and its receptor CCR7 have an
inuence on the migration of antigen-presenting
cells and T lymphocytes from the periphery to
the lymph nodes [77–79]. The mentioned articial approaches combine the time-consuming
cell isolation and culturing steps for the production of articial lymphatic tissue.
A further development of the already referred
methods is the introduction of the idea to combine autologous lymph node fragments and biodegradable scaffolds. There are two promising
ideas combining lymph node fragments and scaffolds. On the one hand, Hadamitzky etal. [80],
who used aligned nanobrillar collagen scaffolds
and, on the other hand, Kwak etal. [81, 82] who
used polycaprolactone (PCL) tubes.
Hadamitzky etal. [80] performed a porcine
model of secondary lymphedema in minipigs.
Here, 10 aligned nanobrillar collagen scaffolds (10–12cm each) were implanted into the
groin of a previously operated and irradiated
minipig. Three months after implantation the
scaffolds were analyzed histologically, the lymphatic function was determined by bioimpedance ratio, and the lymphatic regeneration was
quantied by computed tomography. It was
found that aligned nanobrillar collagen scaffolds provide mechanical support for directed
lymphangiogenesis. The density of lymphatic
vessels increased as well as the lymphatic function improved.
The whole concept of Kwak etal. [81] is provided in Fig. 25.2. A lymphedema patient provides a lymph node from a healthy donor site.
This removed lymph node is then fragmented and
xed inside the PCL scaffolds by using brin
glue (bioarticial lymph node). Several of these
bioarticial lymph nodes are then implanted
close to an artery into the diseased region. In the
following months, the bioarticial lymph nodes
induce growth factor release and regeneration of
the lymphatic system.
In previous studies, Kwak etal. used tubular,
porous PCL scaffold in immunodecient mice in
combination with human lymph node fragments.
After 8 and 16 weeks, samples were taken and
histological and immunohistochemical staining
were performed. It was shown that the combination of lymph node fragments and PCL scaffold
result in higher vascularization as well as presence of lymphatic endothelial cells [82]. These
cells are responsible and essential for building
lymphatic vessels and regenerate lymphatic
function.
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5) Body
regeneration
P. Neßbach and M. M. Aitzetmüller
1) Removal of 1-2 lymph
nodes from a healthy area
2) Fragmentation of lymph
nodes
4) Implantation into the
diseased area
Fig. 25.2 Method for bioarticial lymph nodes according to Kwak etal. [81]
25.5 Conclusions
avoid these risks, in the future, novel translational
3) Preparation as
bioartificial lymph nodes
treatment approaches harnessing the possibilities
Lymphedema patients often go through a long
ordeal. They consult a number of physicians
according to their cancer disease and following
lymphedema symptoms. A well-documented
clinical history and physical examination typically are sufcient to provide clear diagnosis of
chronic lymphedema. In obscure cases, additional lymphoscintigraphy and/or magnetic resonance imaging lead to a diagnosis.
Even after diagnosis, the suffering of patients
with chronic lymphedema is high. The existing
options for treatment often do not contribute to a
signicant improvement in the quality of life.
of regenerative medicine are warranted.
The most innovative regenerative medicine
paradigms are related to cell processing and culturing, which typically leads to a harsh regulatory
situation which is time- and resources consuming. The approaches that combine autologous
lymph node fragments and biodegradable scaffolds therefore are particularly promising. They
do not require problematic regulatory processes
because they are considered medical devices (no
cell processing). Additionally, they promote true
regeneration of the lymphatic system instead of
treating the disease only symptomatically.
Complete decongestive therapy is effective, but is
only symptomatic and needs to be continued lifelong [55, 83]. Microvascular lymph node trans-
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