European Spine Journal (2021) 30:22–33

https://doi.org/10.1007/s00586-020-06596-0

REVIEW ARTICLE

Lumbar interbody fusion: recent advances in surgical techniques

and bone healing strategies
Bin Meng1,2 · Joshua Bunch1 · Douglas Burton1 · Jinxi Wang1 

Received: 1 May 2020 / Revised: 26 August 2020 / Accepted: 5 September 2020 / Published online: 19 September 2020
© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Purpose  Lumbar interbody fusion (LIF) is a treatment option for low back pain secondary to lumbar instability and/or
deformity. This review highlights recent studies of surgical techniques and bone healing strategies for LIF.
Methods  Relevant articles were identified by searching the PubMed database from January 1948 to April 2020, with a
focus on the last 5 years, using the following keywords: LIF approach, LIF cage, stem cells for LIF, biomaterials for LIF,
and osteobiologics for LIF.
Results  LIF procedures were traditionally performed through either a posterior approach (PLIF), or an anterior approach.
Later, the transforaminal LIF approach gained popularity over the PLIF as it entailed less nerve retraction. To minimize
paraspinal muscle dissections, alternative approaches including lateral LIF, oblique LIF, and minimally invasive approaches
have been developed and utilized. These modifications have improved the surgical outcomes of LIF. However, the most recent
rates of non-union after LIF procedures still ranged from 7 to 20% with an even higher incidence in patients with osteopo-
rosis. This review summarizes the advantages and disadvantages of each surgical approach and current efforts to enhance
LIF by improving fusion cage material properties and developing novel osteobiologic products that contain nanomaterials
for controlled release of effective osteogenic proteins and mesenchymal stem cells.
Conclusions  There have been significant advances in surgical technologies for LIF over the past decades. Post-operative
non-union remains a major challenge, which could be addressed by development of more effective surgical techniques,
fusion cages, and bone healing products through joint efforts from spine surgeons, bone biologists, and material engineers.

Keywords  Lumbar arthrodesis · Lumbar interbody fusion · Bone healing · Bone biomaterial · Osteobiologic product

Introduction range between 6.3 and 15.4%. Approximately 75% to 80%

Lumbar spinal disorders are one of the most prevalent mus-
culoskeletal conditions. While substantial heterogeneity
exists among epidemiological studies of lumbar conditions
that limit the ability to pool data, estimates of the 1-year
incidence of a first-ever episode of low back pain (LBP)
* Douglas Burton
dburton@kumc.edu
* Jinxi Wang
jwang@kumc.edu
1
Department of Orthopedic Surgery, University of Kansas
Medical Center, 3901 Rainbow Boulevard, MS #3017,
Kansas City, KS 66160, USA
2
Department of Orthopedic Surgery, The First Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215006,
China
of the adult population may experience LBP at least once in
their lifetime [1, 2]. LBP can be classified into primary (non-
specific/idiopathic) LBP and secondary LBP due to known
causes such as intervertebral disc degeneration (IDD), facet
joint disorders, spinal injury, deformity and instability,
and neuromuscular diseases [3–5]. Primary LBP is mainly
treated by non-surgical modalities, while lumbar spine sur-
geries are considered for secondary LBP following failed
conservative treatments. Lumbar interbody fusion/arthro-
desis (LIF), usually combined with posterior or anterior
instrumentation, is a treatment option to stabilize the pain-
ful motion segment, restore lordosis, correct deformity, and
provide indirect decompression of the neural elements [6, 7].
Several surgical techniques have been developed for
LIF, though there is insufficient evidence to recommend
a standard fusion method. Traditionally, interbody fusion
procedures were performed through an anterior approach

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European Spine Journal (2021) 30:22–33 23
called anterior LIF (ALIF), or a posterior approach called
posterior LIF (PLIF). Later, the transforaminal LIF (TLIF)
technique gained popularity over the PLIF as it entailed less
nerve retraction. To minimize spinal and paraspinal muscle
dissection, alternative approaches have been developed and
used, which include extreme or lateral LIF (XLIF/LLIF)
and oblique LIF (OLIF) [8–12]. Over the past decade or
so, minimally invasive approaches such as minimally inva-
sive TLIF (MI-TLIF) have been further developed and more
widely utilized in clinical practice [13–15].
With continuing improvements in surgical technology and
the design of interbody fusion cages for treatment of low
back pain, there has been an increase in the rate of lumbar
fusions performed over the past decades [16, 17]. However,
surgical complications, particularly post-LIF non-union or
pseudarthrosis, remain a major challenge. Despite the dec-
ades of effort, most recent studies indicated that the rates
of non-union after LIF still ranged from 7 to 20% with a
significantly higher incidence in cases spanning 3 or more
spinal levels [18–21]. The non-union rate of LIF in patients
with osteoporosis was reported to be 29% even in one-level
LIF [22]. Autogenous iliac crest bone grafting (ICBG) has
been used as the gold standard to enhance bony fusion of
affected intervertebral joints. However, the harvesting of
autologous bone is associated with significant risk of mor-
bidity, intraoperative complications, and donor site pain.
Spine surgeons and researchers have been working together
to improve fusion rates.
This review article highlights the recent studies on sur-
gical procedures and the development of novel osteogenic
bioproducts (osteobiologics) and biomaterials utilized in
lumbar fusions, with a focus on LIF. The gaps in our knowl-
edge and possible future studies to bridge the gaps in the
lumbar fusion field are discussed in the Prospects section.
Surgical techniques and clinical outcomes
of LIF
The general procedure of LIF includes the distraction of
suitably prepared intervertebral body space and insertion of
a bone graft and/or cage containing osteogenic materials that
cover the breadth of the bony endplates. Once the interbody
construct is completed, the interbody cage or graft acts as a
central flagpole braced and compressed by “wires” on three
sides under tension: the anterior longitudinal ligament ante-
riorly, the facet joints and their capsules bilaterally, and the
interspinous and supraspinous ligaments posteriorly [23].
Most surgeons augment this intrinsic stability with supple-
mentary posterior or anterior fixation. The recent studies on
the indications, outcomes, and major advantages and disad-
vantages of currently used surgical techniques for lumbar
fusion are discussed below.
Posterior LIF (PLIF)
Indications and operative characteristics
In the 1950s, Cloward [24] described a technique for per-
forming a LIF through a posterior laminectomy access to the
intervertebral disc, which became known as a PLIF. Selected
patients with segmental instability, recurrent disc herniation,
symptomatic spinal stenosis, and pseudarthrosis may benefit
from a PLIF procedure. Contraindications for PLIF surgery
include extensive epidural scarring, arachnoiditis, and active
infection [7]. PLIF procedure was designed to preserve the
facet joints and required nerve root retraction to allow for
adequate disc excision and placement of an interbody graft
or cage. The classic PLIF entry point is illustrated in Fig. 1.
PLIF consists of adequate decompression, complete dis-
cectomy, and spinal fusion with or without supplementary
transpedicular screw/rod stabilization. Fusion is achieved
with either iliac crest autograft, allograft, or with cages filled
with bone graft.
Advantages of PLIF: (1) This approach allows for wide
posterior visualization and circumferential decompression of
the neural elements [25]. (2) A separate incision is unneces-
sary as the spine is already exposed for decompression. (3)
Fusion is in compression.
Disadvantages of PLIF: (1) Epidural bleeding; (2) cage
migration, particularly without posterior instrumentation
[26]; (3) cage subsidence associated with excessive endplate
decortication; (4) epineural fibrosis giving rise to persistent
back and/or leg pain; 5) neurological impairment [27].
Surgical and clinical outcomes of PLIF
A recent comparative study demonstrated that solid spinal
fusion was achieved in 84/95 cases (88.4%) [28]. The most
characteristic radiographic indicator of interbody fusion is
Fig. 1  Technique for posterior lumbar interbody fusion (PLIF).
Access to disc space is more medial requiring retraction of the thecal
sac when the ipsilateral facet joint is intact. IVD: intervertebral disc
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the presence of a “sentinel sign”, bridging trabecular bone
anterior to the intervertebral space [26]. Pseudarthrosis or
non-union is suggested by persistent pain, development or
progression of deformity, loss of disc height, vertebral dis-
placement, implant failure, haloing, migration or resorption
of the bone graft, pedicle screw loosening, and movement
on flexion/extension views [23].
Adjacent segment degeneration (ASD) has been reported
as one of the important sequelae affecting the long-term
results of PLIF. Maruenda et al. [29] reported that reopera-
tion for symptomatic ASD was 9.6% at 5-year follow-up,
24.6% at 10-year follow-up, and 37.5% at 15-year follow-
up. Controversially, other studies suggested that although
LIF was associated with lower disc space height at the
adjacent segment after an average of 13 years of follow-up,
the reduced disc space height had no influence on patient
self-rated outcomes (pain or disability) [30]. The pathogenic
mechanism of ASD has been proposed to be a redistribution
of stress at the neighbouring level, which leads to extended
mobility and increased intradiscal pressure in the adjacent
segments [30, 31]. ASD may also occur in other approaches
of LIF but will not be described repeatedly.
Transforaminal LIF (TLIF)
Indications and operative characteristics
TLIF was originally described by Blume and Rojas and then
popularized by Harms and colleagues as an alternative to
PLIF, which combined anterior/posterior fusion techniques.
Indications of a TLIF approach include all degenerative
pathologies, including broad-based disc prolapses, degen-
erative disc disease, recurrent disc herniation, lumbar spinal
canal stenosis, pseudoarthrosis, segmental spinal instabil-
ity, and symptomatic spondylosis. Contraindications include
extensive epidural scaring, arachnoiditis, conjoined nerve
roots (that may preclude access to the disc space), and osteo-
porotic patients [32].
The TLIF technique accesses the disc via a path that runs
through the posterolateral portion of the vertebral foramen.
Pedicle screw fixation enables disc space distraction and
dynamically restores lumbar lordosis with the interbody
spacer [33]. With a transforaminal approach, unilateral lami-
nectomy and inferior facetectomy along with resection of
the proximal portion of the superior facet are required at the
intended level of fusion to gain access to the intervertebral
disc, preserving the contralateral facet joint. Discectomy,
endplate preparation and insertion of cage(s) packed with
bone grafts are similar to PLIF although done from a more
lateral entry into the disc space. TLIF offers an approach to
the disc space that requires less/no traction on the dura and
traversing nerve roots compared to PLIF (Fig. 2).
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European Spine Journal (2021) 30:22–33
Fig. 2  Technique for transforaminal lumbar interbody fusion (TLIF).
Access to disc space is obtained by removing the ipsilateral facet
joint. This provides a working corridor lateral to the thecal sac, thus
not requiring the need for substantial retraction of the thecal sac.
IVD: intervertebral disc
Advantages of TLIF: TLIF preserves the interlaminar
surface of the contralateral side, which can be used as addi-
tional surface area for the fusion mass [34]. TLIF involves
exposing only the ipsilateral neural foramen, although
bilateral decompression can be performed if needed. This
decreases the risk of incidental neural complications [35].
Consequently, TLIF can be performed safely above L3 with
minimal risk of conus injury and is better suited for reopera-
tions with significant epidural fibrosis because only a one-
sided, lateral dural exposure is needed [32, 36].
Disadvantages of TLIF: The disadvantages of TLIF
include incomplete removal of intervertebral disc, incom-
plete vertebral endplate preparation, and potential occult
injury to the exiting nerve root. However, these are uncom-
mon among experienced surgeons. Classic TLIF is unable
to decompress the contralateral nerve root.
Surgical and clinical outcomes of TLIF
TLIF is significantly better at restoring lumbar lordosis and
spinal sagittal balance among degenerative lumbar scoliosis
(DLS) patients compared to those treated with posterolat-
eral lumbar fusion [37]. This is mainly because TLIF can
restore anterior column height by interbody distraction and
can achieve better restoration of lumbar lordosis by resection
of the posterior facet joints and posterior compression [37].
TLIF is widely used today in lumbar spinal fusion because
of less violation to the spinal canal, compared to PLIF, and
due to less time consumption and morbidity compared to
ALIF [38, 39].
The complication rate in the TLIF group was 14%, includ-
ing haematoma, superficial infections, nerve root lesion,
European Spine Journal (2021) 30:22–33 25
dural tears, and intraoperative pneumothorax which could
be treated with drainage at 2-year follow-up [37].
Anterior LIF (ALIF)
Indications and operative characteristics
ALIF was introduced by Lane and Moore [40] in 1948.
ALIF may be considered as a salvage technique for patients
who present with painful pseudarthrosis following posterior
lumbar fusion [41]. The anterior approach is an excellent
approach for the L5–S1 level, but has poorer access for lev-
els above L3–L4. The disc may be approached anteriorly via
retroperitoneal or transperitoneal routes. The transperitoneal
approach is limited above the L4 level, while the retroperito-
neal approach provides access to all lumbar vertebrae from
L1 to the sacrum. Generally, the retroperitoneal approach
is preferred, while transperitoneal approaches are utilized
mainly in markedly obese patients or when prior retroperi-
toneal exposure has been performed [42]. After completion
of the discectomy and preparation of the endplates, the disc
space is trialed to the desired endplate coverage, height and
lordotic angulation prior to cage or graft placement [43].
Advantages of ALIF: The direct visualization and efficient
access to the anterior column allows for an easier and com-
plete discectomy while offering better distraction to increase
the neuroforaminal volume and to allow the placement of
a large interbody fusion device [44, 45]. This technique
achieves higher fusion rates and reduces iatrogenic trauma to
the paraspinal musculature, posterior spinal nerves, and pos-
terior bony elements [46], better restores lumbar lordosis as
well as coronal and sagittal balance, and reduces anterolis-
thesis [44, 47]. Placing the graft in direct compression with
contact against a larger osseous endplate surface area and a
larger vascular supply increases the fusion potential [41].
Disadvantages of ALIF: The majority of complications
associated with ALIF are due to the surgical approach,
such as post-operative hernias [48], bowel obstruction, iliac
venous thrombosis, urological injury, and retrograde ejacula-
tion [23]. Major vascular complications have been reported
in 0.5–4.0% of cases [49]. One of the main drawbacks of
ALIF is the necessity for a separate posterior incision to
decompress the neural elements or to place pedicle screw
fixation [50].
Surgical and clinical outcomes of ALIF
Interbody fusion rates of ALIF are reported to be higher
than those associated with posterolateral approaches. Jack-
son et al. [43] reported ALIF fusion in 41 out of 43 patients
(95.3%) or 71 of 73 levels (97%), with minor complications.
A randomized controlled trial demonstrated the change in
whole lumbar lordosis was not dependent on the change of
the segmental angle at the fused segment over a 10-year
follow-up period [51].
Extreme lateral LIF (LLIF/XLIF)
Indications and operative characteristics
First introduced by Berjano et al. [52] in 2011, the LLIF
approach is a safe and effective alternative to the anterior
or posterior approaches to lumbar fusion, avoiding the large
anterior vessels and posterior structures. Possible indica-
tions include degenerative disc disease, adult scoliosis, spon-
dylolisthesis, lumbar spondylosis with instability, lumbar
stenosis, adjacent segment disease, trauma, disc replacement
revision surgery, and pseudarthrosis [52]. Another indica-
tion is seen in de novo scoliosis cases as the large, laterally
placed cages permit coronal and some sagittal realignment
of the spine [53].
The patient is placed in a lateral decubitus position. The
surgical pathway for the LLIF approach consists of three
parts: (1) lateral flank, (2) retroperitoneal, and (3) transp-
soas. The first part includes the passage through the obliquus
externus and internus abdominis as well as the transversus
abdominis muscle in a blunt parallel muscle fibre-splitting
technique [54]. During the second part, the important struc-
tures include the subcostal, iliohypogastric, ilioinguinal, and
lateral femoral cutaneous nerves [55]. The third part requires
knowledge of the lumbar plexus, which migrates from a dor-
sal to ventral location from the L1–2 down through the L4–5
disc space [56]. “Neuromapping” around the dilator is a cru-
cial safety element. If the dilatator is in a safe zone, a K-wire
is inserted into the disc through the dilator, and its position is
confirmed with biplanar fluoroscopy. A classic discectomy
is performed, followed by an appropriate lateral-to-lateral
cage placement [53].
Advantages of LLIF: The LLIF technique allows for
access to the anterior and middle columns of the lumbar
spine via a small incision (approximately 3–4  cm) and
access of the intervertebral space with low intraoperative
blood loss [57, 58]. In the lateral position, gravity clears
most of the abdominal content away from the field. The lat-
eral approach allows relatively easy access to multiple levels
from T11 to L4, with a transpsoas approach which preserves
the longitudinal ligaments of the spine, as well as posterior
musculature. In contrast to ALIF, there is no direct trauma
to the abdominal viscera, the peritoneum, great iliac ves-
sels, and sympathetic chain [59]. The advantages of LLIF
also include minimally invasive access to the lumbar spine,
shorter operative times, shorter hospital stays [60].
Disadvantages of LLIF: The LLIF technique has a limi-
tation in cases of severe central stenosis. Venous anatomi-
cal variants and teardrop-shaped psoas with an anteriorly
located plexus can preclude the approach to L4–5. Since the
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iliac crest obstructs the true lateral trajectory, LLIF is not
possible at the L5–S1 level. Given that the psoas is directly
penetrated in this lateral technique, there have been reports
of patients experiencing post-operative hip flexion weak-
ness. Thigh and groin pain may be seen following LLIF if
the genitofemoral nerve is stretched or injured [61, 62].
Surgical and clinical outcomes of LLIF
With optimal technique, long-term follow-up data demon-
strates similar fusion rates in comparison to anterior and
posterior approaches [63]. No statistically significant differ-
ences were found between the different types of graft used
to fill the cages [57]. The most frequent side effect of the
LLIF approach is post-operative “thigh” symptoms, with a
relatively high overall incidence of on average one of five
patients [61]. These so-called thigh symptoms include thigh
paresthesia, thigh numbness, and motor weakness affecting
hip flexion. Most of these sensory and/or motor deficits are
transient with a 50% recovery rate at 3 months and 90%
recovery rate after 1 year [53].
Oblique LIF (OLIF)
Indications and operative characteristics
The oblique trajectory anterior to psoas (ATP) approach for
LIF (OLIF) was first described by Phan and Mobbs, using
it for revision of a posterior non-union [64]. While LLIF is
not amenable at the L5–S1 level due to obstruction by the
iliac crests, the OLIF approach uses a retroperitoneal plane
to access the disc via a corridor anterior to the iliac crests,
between the psoas muscle and the major abdominal vessels.
In contrast to LLIF, no dissection and splitting of the psoas
muscle is required; this theoretically reduces post-operative
pain [64]. Typical indications include degenerative disc dis-
orders, discitis, and pseudoarthrosis at L5–S1, as well as
isthmic spondylolisthesis [65–67]. An intervertebral cage is
inserted following disc space preparation. Subsequent poste-
rior stabilization can be performed via open or percutaneous
procedures depending on the pathology present [68].
Advantages of OLIF: The oblique trajectory allows the
surgeon to avoid surgical trauma to the psoas and lumbosa-
cral plexus, with efficient clearance of the disc space and
application of a large interbody device to produce distrac-
tion for foraminal decompression. The angle of the oblique
approach also allows for a unique view (compared to LLIF)
of the epidural space if desired, facilitating the decompres-
sion and removal of ventral osteophytes and disc herniation
[64]. The OLIF approach is considered a possible solution to
the issues posed by ALIF (iliac vessel and peritoneal injury)
and LLIF (psoas splitting and limited lower lumbar spine
access) [69, 70].
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European Spine Journal (2021) 30:22–33
Disadvantages of OLIF: Complications of OLIF include
post-operative numbness, pain, and leg weakness [11]. If
the retroperitoneal oblique corridor (ROC) is narrow, more
psoas retraction is needed, contributing to an increased pos-
sibility of post-operative neurological complications.
Surgical and clinical outcomes of OLIF
Fusion rates with OLIF have been shown to be 84% or
higher. Operative duration ranged from 55 to 145  min,
while blood loss ranged from 67.8 to 260 ml [59]. Abe et al.
reported the overall incidence of perioperative complications
of OLIF surgery reached 48.3%, of which only 1.9% resulted
in permanent damage among the 155 patients in their study.
The most common complication was endplate fracture/sub-
sidence (18.7%), followed by transient psoas weakness and
thigh numbness (13.5%), segmental artery injury (2.6%),
surgical site infection (1.9%), and reoperation (1.9%) [68].
Summary of surgical techniques and clinical
outcomes
The directions of surgical approach for the above-mentioned
LIF techniques are illustrated in Fig. 3. The main advantages
and disadvantages of the fusion approaches are briefly sum-
marized in Table 1. Importantly, each patient’s individual
pathoanatomy, age, desires, and concerns as well as sur-
geon’s experience should all be factored into the decision-
making process when determining the optimal strategy for
an individual patient to maximize fusion potential while
minimizing risk of complications [71].
Fig. 3  Surgical approaches for lumbar interbody fusions. A tradi-
tional anterior lumbar interbody fusion (ALIF) has been described
with both a transperitoneal as well as retroperitoneal approach. More
recently, oblique lumbar interbody fusion (OLIF) and extreme lat-
eral lumbar interbody fusion (LLIF/XLIF) through a retroperitoneal
approach (dotted arrow lines) have grown in popularity. Posteriorly
based interbody fusion approaches include posterior lumbar interbody
fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF)
European Spine Journal (2021) 30:22–33 27

Table 1  Advantages and disadvantages of various interbody fusion techniques

Fusion technique* Advantages Disadvantages

PLIF Endplates provide large fusion surface area
Compression across interbody
Wide posterior visualization
Decompression of neural elements
No additional anterior-based approach
TLIF Decreased dural and neurological injury rate due to more
lateral entry and less retraction
Increased remaining posterior bony fusion surface area
Decreased soft tissue/paraspinal muscle dissection
Less exposure of midline neural structures
ALIF Reduced blood loss and operating time
Increased fusion rate
Complete disc space preparation
Larger interbody fusion implant
Improved restoration of lumbar lordosis
Decreased trauma to posterior paraspinal musculature and
neural elements
Excellent access to L5–S1
XLIF/LLIF Reduced blood loss, OR times, and hospital stays
Decreased trauma/manipulation to abdominal viscera
Larger interbody fusion implant
Coronal and sagittal correction potential
Decreased trauma to posterior paraspinal musculature and
neural elements
OLIF L5–S1 accessible
No psoas splitting
Minimal peritoneal retraction
Larger interbody fusion implant
Decreased trauma to posterior paraspinal musculature and
neural elements
Increased retraction of thecal sac and neural elements
Epidural bleeding
Cage migration, especially without posterior instrumentation
Post-operative fibrosis/scarring
Incomplete disc space preparation
Potential exiting nerve root injury
Unilateral approach (must perform laminoforaminotomy to
decompress contralateral side)
Incomplete disc space preparation
Anterior approach related complications (ex. hernia, bowel
obstruction, ileus, urological injury, retrograde ejaculation,
vascular injury)
Additional posterior approach necessary for direct decom-
pression of neural elements
Unable to approach L5–S1 routinely (L4–5 can be difficult)
Hip flexion weakness
Thigh and groin pain
Additional posterior approach necessary for direct decom-
pression of neural elements
Hip flexor weakness
Post-operative numbness and pain
Additional posterior approach necessary for direct decom-
pression of neural elements

*PLIF posterior lumbar interbody fusion; TLIF transforaminal lumbar interbody fusion; ALIF anterior lumbar interbody fusion; XLIF extreme
lateral lumbar interbody fusion; LLIF lateral lumbar interbody fusion; OLIF oblique lumbar interbody fusion

Osteobiologics and Biomaterials in LIF
Bone grafts
Bone grafts are widely used in spinal fusion procedures to
enhance the process of bone healing [72, 73]. Although both
autogenous and allogeneic bone grafts can be used for spinal
fusion, autogenous iliac crest bone grafting (ICBG) has been
recognized as the gold standard for lumbar fusion. ICBG is
non-immunogenic, provides osteogenic cells and biological
factors, and serves as a scaffold for the growth of new bone.
However, the harvesting of iliac crest bone is associated with
a risk of intraoperative complications and donor site pain.
The adverse effects of ICBG place a limit on its potential
in spinal fusion and create the need to explore alternative
techniques [73–75].
Bone biomaterials
Bone biomaterial or bone substitute was defined as any
synthetic or natural osteoconductive biomaterials, other
than bone grafts or osteoinductive growth factors, that
can be inserted into bone defects to promote bone repair.
An ideal bone substitute should be biocompatible, be eas-
ily moulded into bone defects, absorbable, radiographi-
cally identifiable, sterilizable, and readily available.
Many biomaterials, such as polyesters, collagen scaffold,
hydroxyapatite (HA), porous β-tricalcium phosphate,
have been used for spinal fusion. It has been recognized
that osteoconductive biomaterial alone is limited to the
healing of a small bone defect and that a combination of
bone biomaterial with osteogenic cells and/or growth fac-
tors provides more favourable outcomes of spinal fusion
[76–78]. Bone biomaterials may enhance spinal fusion
via two mechanisms: (1) biomaterials can serve as a scaf-
fold to promote cell migration on the material surface,
ingrowth of cells and capillaries, cell proliferation, and
osteogenic differentiation of mesenchymal stem cells in
a bone environment. (2) Biomaterials including nanoma-
terials can be used as a carrier of osteogenic proteins to
restrict or control their release [79–82].

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Osteoinductive protein‑based osteobiologics
Urist made the key discovery that demineralized segments
of rabbit bone was capable of inducing new bone formation
when implanted intramuscularly [83]. This early finding was
followed by isolation and purification of bone morphoge-
netic proteins (BMPs) and production of recombinant human
BMP-2 (rhBMP2) for clinical applications [84]. rhBMP2
has been the most widely used osteoinductive growth fac-
tor for spinal fusion in the past two decades. With the ben-
efit of enhanced fusion and the ability to spare ICBG har-
vesting, the United States Food and Drug Administration
(FDA) approved rhBMP2 for anterior lumbar fusion in 2002.
Early studies demonstrated both superior lumbar fusion and
decreased morbidity of rhBMP2 (using collagen-1 as a car-
rier) compared with the gold standard, ICBG (88 vs. 73%)
[85].
After the initial FDA approval, rhBMP2’s role rapidly
expanded into multiple on and off-label uses including cervi-
cal and posterior lumbar fusions. A prospective analysis of
279 consecutive patients with adult spinal deformity showed
no increase in acute major complications, neurological com-
plications, or wound complications at reported doses (poste-
rior dose: 2.5 mg/level, interbody dose: 5 mg/level) [86]. A
literature review did not find definitive association between
rhBMP2 and tumorigenesis [87]. However, some studies
reported the propensity of high-dose rhBMP2 to cause tum-
origenesis and others cited life-threatening complications
(e.g. swelling and swallowing/breathing difficulties) in ante-
rior cervical procedures [88–91]. These conflicting reports
motivate future research with different doses of rhBMP2 and
long-term follow-up in larger patient populations to further
elucidate rhBMP2-associated complications
Prospects
As described above, the rate of bony fusion and functional
improvement of the current treatment modalities are still less
than optimal for long-term outcomes despite recent techni-
cal advancements. Although many strategies could improve
the outcome of spinal fusion, our perspectives will focus on
the further development of interbody cages and biological
products for improved bony fusion and functional outcomes.
Improvement of interbody cages and surgical
techniques
Interbody options include titanium, polyether ether ketone
(PEEK), carbon fibre, bioabsorbable and composite
implants. Advantages and disadvantages exist for these vari-
ous materials. Clinical evidence is growing, but numerous
opinions remain regarding optimal interbody cage designs
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European Spine Journal (2021) 30:22–33
including construction material, shape, and biomechanical
properties as well as expandable versus fixed height cages.
Advantages and disadvantages of PEEK, titanium,
and composite cages
Titanium, PEEK, and composite implants (e.g. NanoMetal-
ene) incorporating both titanium and PEEK are among the
mostly widely used interbody implants [98]. Advantages of
titanium cages include biocompatibility with bone and osse-
ointegration potential [92]. Disadvantages are the radiopac-
ity and increased stiffness compared to cortical bone [93,
94]. PEEK is radiolucent and has a stiffness closer to that of
cortical bone [94, 95]. The radiolucent nature of PEEK is
beneficial given the need for post-operative imaging often
needed in patients undergoing instrumented spinal proce-
dures. Disadvantages include the relative inertness and lack
of osteoconductivity of PEEK as well as a smoother and
more hydrophobic surface, which may affect cage stability
and fusion rates [94, 96].
As a result of the above benefits and drawbacks of each
material, numerous proprietary processing techniques have
been developed by spinal implant companies with the aim to
increase bioactivity and bone ongrowth/ingrowth potential
of interbody implants. Techniques utilized have included
surface modifications through plasma spraying, nano-mod-
ification, 3D-printing porous surfaces, and chemical and
thermal processing [92, 97]. Composite implants composed
of PEEK with titanium surface coating (NanoMetalene)
using titanium nanotopography have been developed to take
advantage of the relative benefits of each material. Recent
ovine models have demonstrated significant bone ongrowth
potential of titanium-coated PEEK implants [98, 99]. Addi-
tionally, Struwe et al. reported that a novel PEEK interbody
cage for PLIF with an impactionless insertion technology
could improve lumbar bony fusion with relief of back pain
and ASD [100].
Expandable versus fixed height cages
An additional design characteristic has been expandable
(dynamic) versus fixed (static) height interbody implants.
The window for bone graft has typically been larger within
fixed cages and thus a relative advantage. Expandable
implants allow surgeons to obtain good bony endplate con-
tact and restoration of disc height with less need for distrac-
tion across pedicle screws or the corresponding vertebral
lamina. Hawasli et al. found a greater increase in disc height
and foraminal height among patients undergoing a minimally
invasive TLIF with an expandable interbody implant com-
pared to a fixed height implant [101]. 3D-printed dynami-
cally semi-crystalline liquid crystal elastomer (LCE) for an
expandable endplate-conforming interbody fusion cage may
European Spine Journal (2021) 30:22–33 29
address vertebral mobilization issue and possibly reduce the
incidence of ASD through more desirable mechanical prop-
erties [102]. In contrast, Gelfand et al. found no difference
in disc or foraminal height change after TLIF with fixed
versus expandable interbody implants [103]. Future large-
scale, multi-centre investigations with long-term follow-up
are required to more objectively evaluate the clinical out-
comes of these newly developed or developing interbody
fusion cages.
Improvement of surgical techniques
Surgical techniques continue to evolve for improvement of
clinical outcomes. Cortical bone trajectory (CBT) screw
insertion through a caudomedial starting point provides
advantages in limiting dissection of the superior facet joints
and reducing muscle dissection, resulting in lower rates of
early cephalad ASD after PLIF (CBT-PLIF) than those using
traditional trajectory screw fixation after PLIF (TT-PLIF)
[104].
Further studies with a larger patient population and longer
follow-up period are required for more accurate comparison
of novel surgical techniques and fusion cages. These future
studies would provide greater insights into the strategies for
increasing fusion rates and reducing back pain, neurological
symptoms and risk of ASD.
Development of more effective osteobiologic
products and bone‑forming stimulators
The success of spinal fusion relies on both surgical pro-
cedure and effective bone grafting or osteogenic products.
Despite the advancements in development of osteoinduc-
tive proteins and osteoconductive biomaterials in the past
decades, there is still no consensus on the type or amount
of osteogenic products that should be used for spine fusion
[105]. Future studies on osteobiologic products should
include the following areas.
Discovering novel osteogenic proteins
Due to the concerns about high-dose rhBMP2-associated
tumorigenesis and other complications, further research is
needed to explore novel osteogenic proteins or to develop a
combination of rhBMP2 and other osteogenic factors that
allow for a reduction in the dose of rhBMP2 while achiev-
ing improved spinal fusion. A recent study demonstrated
that activin A/BMP2 chimera (AB204) exhibited better bony
fusion than rhBMP2 alone at a low dose (3.0 μg) in a rat
model of posterolateral spinal fusion [72]. Additional studies
are required to explore other osteogenic proteins for spinal
fusion.
Developing novel biomaterials and controlled release
techniques
Collagen, ceramics, and synthetic polymers have all been
used to deliver proteins into a bone environment to promote
bone healing or fusion. However, many biomaterials cur-
rently used in animal and human studies vary in their ability
to resorb and remodel. Delivery materials that have little or
no binding affinity for rhBMP2 may result in a burst release
shortly after implantation. This may lead to supraphysi-
ological dosages of rhBMP2 causing some of the reported
complications such as seroma formation and an exagger-
ated inflammatory response [105]. Further development of
nanomaterials that can restrict the movement of osteogenic
proteins, confine them to specific location, and allow for a
time-dependent gradual release (controlled release) would
address these issues.
Defining the role of mesenchymal stem cells in spinal
fusion
Mesenchymal stem cell (MSC)-based therapies for disc dis-
eases have largely focused on disc regeneration, with much
less attention to spinal fusion in the past years. Recent stud-
ies on MSC-based therapies for spinal fusion in animal mod-
els and human clinical trials have shown that MSCs could be
potentially effective for spinal fusion [106, 107]. MSCs can
be used safely and effectively for intervertebral disc repair
and spinal fusion. In certain studies, however, MSCs did
not show improved results compared to existing treatments
[106–108]. Future studies should focus on the mechanisms
of action of MSCs for spinal fusion in large-scale studies
with long-term follow-up.
Electrical stimulation
Electrical stimulation technologies, particularly direct cur-
rent stimulation (DCS), may increase the rate of spinal
fusion in both preclinical and clinical studies [109].
The proposed comprehensive strategies for improving
fusion rates and clinical outcomes are summarized in Fig. 4.
Conclusions
With continuing improvements in surgical technology and
the design of fusion cages for treatment of degenerative lum-
bar disorder-associated low back pain, there has been an
increase in the rate of LIF performed over the past decades.
However, surgical complications, particularly bony non-
union or pseudarthrosis, remain a major challenge. Future
studies should focus on further improvement of fusion
cages and surgical techniques, discovery of more effective
13

30
Fig. 4  A diagram summarizing proposed strategies for the enhance-
ment of lumbar interbody fusion (LIF), which include the improve-
ment of fusion cage material properties and the augmentation of
osteogenic potential of fusion implants assisted with electrical stimu-
lation. IVD: intervertebral disc
osteogenic factors with fewer side effects, development of
novel biomaterials for controlled release of osteogenic pro-
teins, and defining the role of MSCs in lumber fusion.
Acknowledgements  This work was supported in part by the Mary and
Paul Harrington distinguished Professorship Endowment as well as the
Allie and Marc Asher Orthopedic Research Endowment. The authors
thank Drs. Yi Feng and Mingcai Zhang for their expert drawing of
illustrations.
Compliance with ethical standards  28:222–225. https​://doi.org/10.1097/bsd.00000​00000​00028​9
Conflict of interest  All the authors state that they have no conflicts of
interest.
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