J Shoulder Elbow Surg (2019) 28, 2041–2052

www.elsevier.com/locate/ymse

BIOLOGIC THERAPY REVIEWS

The role of biologic agents in the management of

common shoulder pathologies: current state and
future directions
James B. Carr II, MD*, Scott A. Rodeo, MD

Department of Sports Medicine and Shoulder Surgery, Hospital for Special Surgery, New York, NY, USA

The field of orthopedic surgery has seen a rapid increase in the use of various biologic agents for the
treatment of common musculoskeletal injuries. Most biologic agents attempt to harness or mimic natu-
rally occurring growth factors, cytokines, and anti-inflammatory mediators to improve tissue healing and
recovery. The most commonly used biologic agents are platelet-rich plasma and cells derived from bone
marrow aspirate and adipose tissue. These agents have become increasingly popular despite a relative
dearth of clinical data to support their use. Much confusion exists among patients and physicians in
determining the role of these agents in treating common shoulder pathologies, such as glenohumeral
osteoarthritis, rotator cuff tears, and tendinopathy. This article reviews the basic science and clinical ev-
idence for the most commonly used biologic agents in the management of common shoulder pathology.
Ó 2019 Published by Elsevier Inc. on behalf of Journal of Shoulder and Elbow Surgery Board of
Trustees.
Keywords: Platelet-rich plasma; bone marrow aspirate concentrate; mesenchymal stem cells; rotator cuff
tear; glenohumeral arthritis; rotator cuff impingement

Biologic agents represent an emerging treatment mo- regeneration is of special interest to physicians who treat
dality for a variety of musculoskeletal conditions. These patients with musculoskeletal injuries.
agents include naturally occurring growth factors and anti- An important feature of commonly used agents, such as
inflammatory mediators that can potentially accelerate tis- platelet-rich plasma (PRP) and bone marrow aspirate
sue healing and recovery. They may act through a variety of products, is their autologous nature. The most commonly
mechanisms, including increased angiogenesis, matrix used autologous biologic agents in orthopedic surgery are
synthesis and remodeling, cell recruitment, and alteration PRP and cell preparations derived from bone marrow or
of inflammatory markers and metalloproteinases. Their adipose tissue. Each biologic agent is unique in its protein
possible role in pain reduction, tissue healing, and tissue and cellular composition and its ability to modify the local
tissue environment.
Although biologic agents have great promise as an
*Reprint requests: James B. Carr II, MD, Department of Sports Med- innovative treatment option, their widespread use has out-
icine and Shoulder Surgery, Hospital for Special Surgery, 535 E 70th St,
New York, NY 10021, USA.
paced the available clinical evidence. There has been a
E-mail address: [email protected] (J.B. Carr). rapid growth in the number of available agents, with growth

1058-2746/$ - see front matter Ó 2019 Published by Elsevier Inc. on behalf of Journal of Shoulder and Elbow Surgery Board of Trustees.
https://doi.org/10.1016/j.jse.2019.07.025
2042 J.B. Carr II, S.A. Rodeo

largely resulting from aggressive direct-to-consumer mar- PRP therapy

keting leading to patient demand rather than robust clinical
data. There is an increasing body of basic science studies
that support a potential role for these agents in the treat- Background
ment of various musculoskeletal injuries; however, high- PRP is an autologous blood sample that has a higher con-
quality clinical data to support their regular use are lacking. centration of platelets compared with baseline whole
It is incumbent on practitioners to understand the landscape blood.14,64 As an autologous blood product, it is rich in
of currently available products and the relevant clinical growth factors that can potentially modulate the inflam-
data. matory pathway and allow improved healing of tendon,
Further confusion is introduced by inconsistent and ligament, muscle, and bone.1,12,48,51 The potential for
often poorly understood terminology. Patients often augmented healing and a relatively low risk profile make
collectively refer to all biologic agents as ‘‘stem cell PRP an especially appealing biologic agent.
therapy.’’ It should be understood that the number of true PRP is typically prepared by obtaining autologous whole
stem cells by formal criteria is very small with currently blood from a patient and then completing a 1- or 2-step
available, minimally manipulated products.43 This wide- centrifugation process to separate plasma from leukocytes
spread misconception among patients, practitioners, and and red blood cells. The centrifugation process separates
industry is due to the combination of our currently and concentrates platelets, which contain numerous cyto-
incomplete understanding of ‘‘biologics’’ and the aggres- kines in their alpha granules, including transforming
sive marketing by both industry and physician practitioners growth factor b, basic fibroblast growth factor, and platelet-
who use potentially misleading advertisements that incor- derived growth factor, which can stimulate healing and
rectly label products as stem cell therapy to attract patients. promote growth of muscle and tendon.24 The potential to
Physicians must be well educated in the differences be- deliver a high concentration of various growth factors
tween various products and understand the pros and cons of makes PRP especially appealing in the treatment of rotator
each approach. cuff tears and tendinopathy given the poor healing capacity
Biologic agents have been used to treat a variety of of the rotator cuff.
orthopedic conditions, including osteoarthritis (OA), ten- Generally, there are 2 main types of PRP based on the
dinopathy, ligament injuries, and various inflammatory white blood cell concentration: leukocyte-rich PRP (LR-
conditions. The shoulder is an area in which biologic agents PRP) and leukocyte-poor PRP. Leukocyte-poor PRP con-
are especially appealing. Rotator cuff tendinopathy, rotator tains only the pure plasma layer of the PRP preparation,
cuff tears, subacromial impingement, and OA are extremely whereas LR-PRP includes some of the leukocyte-
common upper-extremity injuries with a substantial health containing buffy coat layer.52 Although leukocytes are
care burden. Although not as common as OA of the hip or important in wound healing and tissue repair, they may also
knee, shoulder OA has been estimated to affect up to 32.8% induce an excessive inflammatory response.64
of individuals older than 60 years.45,76 Rotator cuff tears One significant limitation of PRP is the inherent vari-
occur in over 20% of the general adult population, with a ability in the final composition, which is influenced by
progressively higher incidence as age increases.17,69,87 The numerous factors. Patient-specific factors include age, sex,
rotator cuff also undergoes a variety of tendinopathic and recent activity level, and recent diet.94 Preparation-specific
avascular changes during the aging process, which can factors include the type of collecting tube, centrifugation
result in partial- or full-thickness rotator cuff tears. These speed, and number of centrifugation cycles.4,75 Some
tendinopathic changes can lead to reduced intrinsic healing studies have even shown a wide variation in PRP compo-
potential following surgical repair, as evidenced by a high sition in separate samples obtained from the same patient.64
rate of healing failure after repair.20,27,39,88 These chronic This variety in PRP composition makes it difficult to
changes and poor healing capacity make the rotator cuff an generalize findings across research studies and is an
especially appealing target for biologic agents. inherent limitation in the field of PRP research.
This article reviews the role of biologic agents in the
treatment of the most common shoulder pathologies, Basic science evidence
including rotator cuff tendinopathy, rotator cuff tears, and The clinical use of PRP is largely based on strong in vitro
OA. The goals of this review are as follows: (1) to help support of its positive effects on tenocytes and myocytes. In
physicians better understand the appropriate terminology vitro studies show that tenocytes exposed to PRP have
for the most commonly used biologic agents, (2) to review increased cell proliferation and matrix synthesis, which
the current literature on the use of various biologic agents could potentially lead to improved tendon regeneration or
in the treatment of the most common shoulder pathologies, healing.3,29 Adult tendons also include a small number of
and (3) to discuss emerging therapies and potential future tendon stem and/or progenitor cells, which can be induced
applications of biologic agents in the management of these to active tenocytes by PRP.98,101 The potential positive ef-
shoulder pathologies. fect of platelet-derived factors and the induction of tenocyte
Biologic agents and shoulder pathology 2043

progenitor cells to mature tenocytes in vitro make PRP an reducing postoperative pain and improving healing rates,
especially appealing agent in the treatment of rotator cuff results have been tempered by the heterogeneity of these
tendinopathy and tears. studies.5,36,68 Studies often differ in underlying tendon
pathology, repair technique, postoperative rehabilitation,
Clinical evidence and PRP composition, making it difficult to make com-
Although PRP has shown promising results in vitro, the parisons between studies and to establish firm
clinical results of PRP in the treatment of various shoulder conclusions.
pathologies have been highly variable. The theoretical Multiple studies have shown no benefit of platelet-rich
ability to reduce pain and induce a more favorable healing fibrin matrix in the rotator cuff tendon healing rate or
environment makes PRP especially appealing in both the functional outcomes.35,79 However, PRP injections after
nonoperative and operative management of rotator cuff arthroscopic rotator cuff repair have shown some short-
disease. Regarding nonoperative management of rotator term benefits, including reduced pain and improved
cuff disease, PRP has been studied as an alternative to functional scores, yet these results have generally not been
subacromial corticosteroid injections (CSIs). Shams reproduced with long-term follow-up. Randelli et al78
et al84 conducted a prospective, randomized controlled performed a prospective, double-blinded, randomized
study to compare subacromial PRP injections vs. CSIs in 40 controlled trial investigating clinical outcomes following
patients who had symptomatic partial rotator cuff full-thickness arthroscopic rotator cuff repair with or
tears. Pain scores and patient-reported outcomes were without PRP injections. Pain scores were lower for the
recorded at 6, 12, and 24 weeks after injection. Both in- PRP group up to 30 days after surgery, and some outcome
jection groups demonstrated a statistically significant scores were significantly higher 3 months after surgery.
improvement in clinical outcomes compared with the pre- However, there was no difference in all clinical outcome
injection state. Although PRP showed a statistically sig- measures at 6, 12, and 24 months postoperatively. Simi-
nificant improvement in outcome and pain scores at 12 larly, a recent prospective randomized study by Malavolta
weeks, there was no difference between the 2 groups at 24 et al62 reported clinical and structural outcomes following
weeks. This study suggests that PRP may be an appropriate arthroscopic single-row rotator cuff repair augmented with
substitute for CSIs, especially in patients for whom corti- PRP injections with 5-year follow-up. No differences in
costeroid therapy is contraindicated. PRP may also have the clinical outcome scores or retear rates were found at any
added benefit of preventing iatrogenic tendon weakening, time point up to 5 years after surgery. Verhaegen et al89
which is a concern with excessive corticosteroid ther- examined the use of PRP after arthroscopic needling of
apy.21,30,31 In addition, PRP injections have been investi- rotator cuff calcific deposits. All patients improved
gated in the nonoperative treatment of a variety of significantly with no difference in rotator cuff defects up
tendinopathies, including rotator cuff tendinopathy, with to 1 year after the procedure regardless of whether the
LR-PRP more commonly showing favorable results.28 patient received a PRP injection.
PRP was found to be efficacious in the management of Despite these mixed clinical results, some studies have
shoulder adhesive capsulitis in a randomized trial per- shown improved healing with decreased rates of failed healing
formed by Kothari et al.54 They randomized 195 patients following PRP augmentation of arthroscopic rotator cuff
with shoulder adhesive capsulitis into 3 groups receiving repair. Jo et al42 showed a significantly lower failure rate (20%
either an intra-articular PRP injection, an intra-articular vs. 55.6%) and increased supraspinatus cross-sectional area 1
CSI, or ultrasound therapy. Treatment with a PRP injection year after PRP injection vs. no injection with repair of large to
led to statistically significant improvements over CSI and massive rotator cuff tears. Of note, the speed of healing and
ultrasound therapy in passive range of motion, active range the overall clinical outcomes were similar between groups
of motion, pain scores, and patient-reported functional except for overall shoulder function scores at 1-year follow-
measures at 12 weeks. One significant limitation of this up. Although studies have shown a decreased rate of incom-
study was the lack of long-term follow-up. plete or failed healing following PRP injection, the clinical
Unfortunately, such encouraging nonoperative results significance of this is uncertain because many studies have
have not been consistently reproduced with PRP injections. shown that clinical outcome scores do not always correlate
Kesikburun et al46 performed a double-blinded, randomized with successful rotator cuff healing.27,44,74,88,93
controlled trial of 40 patients with rotator cuff tendinopathy Finally, conclusions from systematic reviews and meta-
receiving either PRP or a saline solution placebo injection analyses have been mixed when analyzing the role of PRP
along with following a physical therapy program. There in surgical management of rotator cuff tears. A meta-
were no differences between the groups in functional analysis by Zhao et al99 reviewed 8 randomized controlled
outcome scores or pain scores at any time point within 1 trials comparing arthroscopic rotator cuff repairs with or
year after injection. without PRP injections. No difference was found in
Clinical data to support the role of PRP in surgical outcome scores or structural healing rates. A more recent
management of rotator cuff tears are equally mixed. systematic review by Hurley et al35 concluded that PRP
Despite a growing number of studies showing efficacy in injections resulted in improved healing rates for small to
2044 J.B. Carr II, S.A. Rodeo

medium rotator cuff tears, improved pain scores, and better

tempered by clinicians and patients. Although basic science
clinical outcomes. Their analysis included 18 randomized
literature supports a potential role in the management of
controlled studies with 1147 patients. Conversely, a meta-
rotator cuff tears, robust clinical data are lacking to support
analysis by Saltzman et al81 in 2016 found no difference
their widespread use. It may be reasonable to consider a
in clinical outcomes after administration of PRP injections
PRP injection in patients who have a contraindication for
following arthroscopic rotator cuff repair. The heterogene-
CSIs, in the setting of revision rotator cuff surgery, or in
ity in conclusions is likely attributable to the wide vari-
patients who have risk factors for poor healing. Although it
ability in patient factors (age, sex, tendon pathology, and
has not been directly studied in a clinical setting, PRP may
medical comorbidities such as smoking and diabetes), type
have a role in the management of glenohumeral arthritis
of PRP, and outcome measures used, which illustrates the
given its positive effects on symptoms in patients with OA
unclear role of PRP in the current management of rotator
of the knee.19,56,85 The positive effect on symptoms of OA
cuff tears.
is likely due to the presence of anti-inflammatory mediators
in PRP. Regardless of the setting or clinical indication,
Future approaches for PRP
physicians must use PRP with tempered and realistic ex-
As previously stated, a major disadvantage of PRP is the
pectations until more rigorous evidence is available to
variability of composition between patients. To reduce or
define the optimal formulations for various conditions.
eliminate this negative feature of PRP, recent efforts have
focused on the development of an ‘‘off-the-shelf’’ allogeneic
PRP product. Allogeneic PRP is particularly appealing
because it allows for standardization of PRP preparation and Cell-based therapy
composition. A 2017 study by Kieb et al47 introduced allo-
geneic PRP powder as a method to standardize PRP growth ‘‘Stem cell therapy’’ is perhaps one of the biggest catch-
factor concentrations. They created lyophilized PRP powder phrases in the landscape of modern medicine. Aggressive
using 12 pooled platelet concentrates from different donors marketing and direct-to-consumer advertising have led to
and demonstrated consistently elevated growth factor con- an explosion of interest among the lay public, leading to
centrations compared with whole blood. Theoretically, this misguided optimism and often unrealistic expectations.
preparation of PRP could allow physicians to choose the Furthermore, many patients lump all biologic agents into
exact composition of PRP to apply a defined content of the category of stem cell therapy despite the presence of
growth factors based on the specific tissue being treated. very few, if any, stem cells in many biologic products. The
Jo et al41 specifically analyzed allogeneic PRP in vitro and definition of a stem cell is also complex and often poorly
in vivo for the treatment of rotator cuff repair. Allogeneic PRP understood. Therefore, patients and physicians alike are
was obtained from 2 healthy donors and screened in a similar often confused about which treatments can accurately be
fashion to an allogeneic blood transfusion. This preparation called ‘‘stem cell therapy.’’
method also has the benefit of a known composition, which The definition of a stem cell is complex. Both molecular
eliminates the variability seen in autologous harvesting. In criteria and functional criteria have been used to define a
their study, human allogeneic pure PRP led to pleiotropic ef- stem cell. At a minimum, a stem cell must possess the
fects on human rotator cuff tenocytes in vitro. Allogeneic PRP ability for self-renewal and multi-lineage differentiation
injection was then administered to 17 patients with rotator cuff along various mesenchymal cell lineages, including osteo-
pathology and compared with a matched control group blasts, adipocytes, and chondrocytes. Minimal criteria
receiving CSIs. Both groups showed significantly improved defined by the International Society for Cell Therapy
pain and outcome scores, with CSI showing improvement include the ability of the cell to adhere to tissue culture
sooner and PRP showing longer-lasting results up to 6 months. plastic, tri-lineage differentiation as noted earlier, and the
No adverse events were seen after allogeneic PRP adminis- presence of a specific cell surface marker profile.22 It
tration. Although more rigorous studies are needed, the use of should be noted that these minimal criteria were defined for
allogeneic PRP appears to be safe and potentially efficacious mesenchymal ‘‘stromal’’ cells and were described for
in preliminary studies. cultured cells. Therefore, the term ‘‘stem cell’’ should not
Other future directions of blood-derived biologic agents even be used for the minimally manipulated preparations
include autologous conditioned serum and autologous currently available in the United States.
protein solution. Although there are some emerging basic It is critically important to distinguish minimally
science data to support the theoretical advantages of these manipulated cell preparations from laboratory-prepared cell
approaches, very few high-quality clinical data are populations that undergo cell sorting and culture expansion.
currently available to support their use. The current regulatory environment in the United States
does not permit ex vivo culture expansion, and thus,
Conclusions virtually all ‘‘point-of-care’’ autologous preparations used
Given the wide variety of clinical results for PRP injections in the United States (ie, bone marrow, adipose, and blood)
for various shoulder pathologies, expectations must be contain very few true stem cells by formal criteria. In fact,
Biologic agents and shoulder pathology 2045

some authors recommend abandonment of the term ‘‘stem at the time of surgical intervention. Second, it contains a small
cells’’ when using the currently available minimally population of mesenchymal stromal cells (MSCs) and pro-
manipulated cell preparations. Rather, the term ‘‘connective genitor cells, which can potentially facilitate healing.71 Third,
tissue progenitor’’ cell has been suggested to be more BMAC has been shown to contain more growth factors and up
appropriate. Connective tissue progenitors are defined as a to 3 times more nucleated cells than PRP.60,100
heterogeneous population of tissue-resident cells that can BMAC can be easily harvested from multiple sites,
proliferate and generate progeny with the capacity to including the anterior superior iliac crest or posterior su-
differentiate into 1 or more connective tissues. These cells perior iliac crest, proximal humerus, intercondylar notch or
are present in many tissues and do have some limited ca- distal femur, proximal tibia, and calcaneus.7,10,97 The iliac
pacity for tissue repair, but they should be distinguished crest is often the preferred site of harvest because of its ease
from pluripotent stem cells. Connective tissue progenitors of access and superior yield of MSCs compared with
do not possess the characteristics of self-renewal or the peripheral sites.66 Harvest can be performed at the time of
ability to reconstitute all the parenchymal cells of the surgery or as an isolated procedure. At least 60 mL of bone
specific tissue. marrow aspirate must be harvested to obtain an adequate
There are 2 further inherent limitations of most stem cell sample for the concentrated product. Performing multiple
therapies. First, stem cells may change behavior once they small-volume aspirations with small syringes has been
are dissociated from their local environment. Second, the shown to result in a 300% increased concentration of pro-
new environment often lacks the appropriate signaling cells genitor cells compared with single large-volume aspira-
or factors to induce differentiation and function of the cells. tions.33 The aspirate is then processed through a series of
Therefore, merely transferring cells to a new environment mesh filters and tubes, followed by centrifugation, until
will likely be less effective without the appropriate about 6 mL of BMAC is produced for subsequent use.
signaling factors to guide appropriate differentiation and Preparation and administration of BMAC do not require
biologic activity at the desired site. It is likely that the approval by the US Food and Drug Administration (FDA) if
principal effect of cell therapy is via a paracrine mecha- it is processed using only centrifugation (‘‘minimal
nism, whereby the cells produce soluble factors that affect manipulation’’) and used in a homologous manner. This
the biologic activity of local and distant host cells. The makes it one of the few FDA-compliant procedures that can
transplanted cells may also have an immunomodulatory acquire both progenitor cells and growth factors. However,
effect on the local environment. there are several important drawbacks to BMAC. First,
Autologous sources of stem cells available to clinicians obtaining BMAC is a painful procedure that usually re-
in the United States include cells derived from bone quires some amount of sedation, making it more chal-
marrow, adipose tissue, and peripheral blood. There is lenging to use in an outpatient clinic. Second, it requires a
some potential to derive stem cells from umbilical cord harvesting and preparation kit, which increases cost. The
blood and amniotic tissues, although robust clinical data most important limitation is that there are a very small
on these cell sources are currently lacking. Cells derived number of stem cells by formal criteria in the final cellular
from these various sources exhibit some differences in composition. Progenitor cells have been found to comprise
biologic activity and likely have different effects in only 0.001% to 0.01% of total cells in the prepara-
different target tissues. Furthermore, numerous factors tion.11,63,77 However, BMAC has been shown to have a very
affect the number and biologic activity of cells derived high concentration of growth factors, including platelet-
from different tissues, including patient sex, age, and derived growth factor, transforming growth factor b, and
comorbidities.53 It has become increasingly clear that a bone morphogenetic proteins 2 and 7, which have been
much more nuanced and refined definition and charac- reported to have anti-inflammatory and anabolic
terization of ‘‘stem cells’’ is required to optimize the effects.38,65,83 In addition, some BMAC preparations contain
application of cell therapy. The current section will focus a considerable concentration of interleukin-1 receptor
on the most commonly used sources of cell-based thera- antagonist, which may be instrumental in reducing the local
pies, bone marrow and adipose tissue, followed by a brief pain response.92
discussion of future directions for cell-based therapy,
including leveraging the local stem cell niche and um- Basic science evidence
bilical cord blood cell therapy. BMAC has been investigated in the treatment of knee OA,
cartilage deficiency, and tendon healing, including rotator
cuff healing. Basic science evidence to support the use of
Bone marrow–derived cell-based therapy BMAC in the management of shoulder pathology is scarce,
but there are some promising early data, with most studies
Background analyzing the role of BMAC in rotator cuff healing
Bone marrow aspirate concentrate (BMAC) is an increasingly augmentation. Liu et al60 investigated supraspinatus tendon
popular biologic adjuvant with unique advantages. First, it is healing with PRP and BMAC in a rabbit model. Tendon
an autologous product that can be obtained with relative ease repairs augmented with BMAC alone or with BMAC and
2046 J.B. Carr II, S.A. Rodeo

PRP showed superior biomechanical properties compared cuff tear. Pain and outcome scores were significantly
with repairs augmented with PRP alone or normal saline improved at 1 month and up to 2 years compared with pre-
solution. BMAC-treated samples demonstrated superior injection levels. Although the results are promising, the
collagen fiber continuity and orientation compared with study was also limited by large heterogeneity in the patient
control samples. BMAC also contained significantly higher population and the lack of a control group.
levels of several growth factors compared with PRP. The most robust clinical study supporting the use of
Kim et al49 studied the effects of BMAC-PRP on mesenchymal stem cells in rotator cuff repair was per-
tendon-derived stem cells and found that the BMAC-PRP formed by Hernigou et al.32 A total of 45 patients under-
solution enhanced proliferation and migration of tendon- went single-row rotator cuff repair augmented by
derived stem cells while preventing aberrant chondro- concentrated mesenchymal stem cells obtained from bone
genic and osteogenic differentiation. This finding suggests marrow, whereas 45 patients underwent single-row repair
a possible mechanism for a clinical benefit of BMAC-PRP without augmentation. Patients treated with concentrated
in the healing of rotator cuff tears. MSCs demonstrated superior tendon healing and enhanced
McDougall et al67 reported the ultrasonographic quality of the repaired tendon on magnetic resonance im-
appearance of canine supraspinatus tendons with tendin- aging (MRI) and ultrasound. Healing at 6 months was
opathy following BMAC-PRP injection. They found that a demonstrated by 100% of shoulders in the cell treatment
BMAC-PRP injection was associated with improvements in group compared with 67% of shoulders in the control
supraspinatus tendon size, fiber pattern, and echogenicity group. Furthermore, at 10-year follow-up, 87% of repairs
up to 90 days after injection. remained intact in the cell treatment group whereas only
A recent study by Ichiseki et al37 examined the anti- 44% of repairs were intact in the control group. Long-term
inflammatory and chondroprotective effects of gleno- maintenance of tendon integrity was directly correlated
humeral MSC injections in a rat shoulder arthritis model. with a higher number of implanted cells.
Intra-articular injection of MSCs reduced inflammatory
markers, increased cartilage protective factors, and inhibi- Conclusions
ted central sensitization of pain. An important limitation of BMAC has the unique advantage of containing a very
the study was the lack of information on the source of the small population of mesenchymal stem cells and a high
MSCs. Nonetheless, these results are a promising step and proportion of various growth factors, but its true clinical
reveal the multifactorial potency of MSCs. efficacy is still largely unknown. High-quality studies with
appropriate control groups are needed to better define its
Clinical evidence clinical role. A critical deficiency in the current literature
Clinical evidence for BMAC in the management of shoul- is the lack of information correlating the composition and/
der pathology is limited to a few small case series. Kim or biologic activity of marrow-derived cells and clinical
et al48 performed a prospective, nonrandomized, single- outcomes. Furthermore, obtaining BMAC is an expensive
blinded study to compare BMAC-PRP injections vs. procedure with unknown cost-effectiveness. Although
shoulder exercises in the treatment of partial rotator cuff BMAC is FDA approved and merits further investigation,
tears. Twelve patients with a partial rotator cuff tear its role in rotator cuff repair augmentation is largely un-
received a BMAC-PRP injection whereas 12 patients per- known at this time.
formed rotator cuff exercises alone for 3 months. Pain and
functional outcome scores were improved in both groups Adipose tissue–derived cell-based therapy
and were only significantly improved in the injection group
at the 3-month time point. Change in tear size did not Background
significantly differ between groups at any time point. Adipose tissue is another frequent source for cell harvest.
Ellera Gomes et al26 performed one of the first studies to Currently available systems for adipose tissue–derived cell-
investigate BMAC and rotator cuff healing. They used based therapy produce a stromal vascular fraction, which is
BMAC augmentation in 14 patients following mini-open, a heterogeneous cell population that includes mature adi-
transosseous suture repair for the treatment of a full- pocytes, fibroblasts, endothelial cells, and adipose-derived
thickness rotator cuff tear. Tendon integrity remained intact stem cells.95 Enzymatic digestion followed by subsequent
in all patients at 1 year after surgery, but 1 patient required culture expansion is required to isolate the desired popu-
revision at 2 years’ follow-up. This study was limited by lation of adipose-derived stem cells, but such ‘‘manipula-
the lack of a control group, but it was one of the first to tion’’ is currently not allowed by the FDA.
demonstrate that BMAC could be safely used as an
augmentation to rotator cuff repair. Basic science evidence
Centeno et al9 performed a prospective multicenter Adipose-derived MSCs have been frequently investigated
study investigating results after BMAC injection in 115 in various animal models focused on tendon healing, with
patients with glenohumeral OA with or without a rotator mostly favorable results. Lee et al58 reported the effects of
Biologic agents and shoulder pathology 2047

implanted human adipose-derived MSCs in rats with iat- the control group (28.5%) was found on 1-year follow-up
rogenic Achilles tendon injury. Transplantation of human MRI. This study suggests that MSCs may safely increase
adipose-derived MSCs led to improved biomechanical postoperative rotator cuff healing yet clinical outcomes
healing and expression of human-specific type I collagen may not be similarly improved despite the increased
and tenascin C for at least 4 weeks after implantation, healing rate.
suggesting that transplanted MSCs may be able to differ-
entiate into the tenogenic lineage while contributing their Future approaches to use of cell-based therapy
own proteins to tendon healing. The field of cell-based therapy is rapidly evolving as new
Rothrauff et al80 investigated the effects of adipose- technology emerges. One promising frontier for cell-based
derived MSC injection following rotator cuff repair in a therapy is the ability to leverage the intrinsic stem cell
rat model. Adipose-derived MSCs increased the bone niche. It is well established that many tissues harbor a small
mineral density of the proximal humerus in the setting of population of intrinsic progenitor cells that are associated
chronic rotator cuff tears but not acute rotator cuff tears. within the walls of blood vessels. These cells are normally
The MSCs did not enhance the histologic appearance or quiescent but can potentially be stimulated during tissue
structural properties in either acute or chronic tears. Oh injury and repair. For example, Eliasberg et al25 reported
et al72 applied adipose-derived MSCs following rotator decreased rotator cuff fatty atrophy following rotator cuff
cuff repair in a rat model and found increased load to repair augmented with perivascular MSCs in a murine
failure, increased compound muscle action potential, and model. It is believed that the local microenvironment may
decreased fatty infiltration of the muscle in the MSC- contain the necessary signaling factors to induce biologic
augmented repair group compared with a group with activity of these cells in the setting of tissue injury and
isolated repair and a group with isolated MSC repair. Recently, the subacromial bursa has been identified
injection. Conversely, Mora et al70 found no significant as a local source of mesenchymal stem cells in the shoul-
differences in supraspinatus tendon biomechanical prop- der.23,59,86 Harnessing these intrinsic stem cells would be
erties after rotator cuff repair augmented with adipose- an alternative approach to the use of exogenous cell sour-
derived MSCs. There was also no difference in ces. The current challenge is to identify methods to stim-
histologic collagen orientation, but the MSC group did ulate the intrinsic stem cell niche.
show less histologic evidence of inflammation. Umbilical cord blood is another emerging source of
MSCs owing to its ease of availability, high proliferation
Clinical evidence capacity, and low immunogenicity.57,91 Kwon et al55
Although adipose-derived mesenchymal stem cell ther- investigated the effect of umbilical cord blood–derived
apy is largely considered investigational at this stage in MSCs on chronic rotator cuff tears in a rabbit model.
its development, a few clinical studies have investigated Compared with controls, rabbits injected with MSCs
its efficacy in treating various shoulder ailments. demonstrated newly regenerated type I collagen fibers,
Recently, Jo et al40 reported a clinical study investi- improved cell proliferation, angiogenesis, and an improved
gating the effects of an intratendinous injection of walking distance and mean walking speed. Similarly, Park
autologous adipose-derived MSCs in patients with par- et al73 reported the regenerative effects of a single human
tial-thickness rotator cuff tears. Medium- and high- umbilical cord blood MSC injection in rabbits with full-
concentration injections resulted in significantly reduced thickness subscapularis tears. Injection alone resulted in
shoulder pain, improved clinical outcome scores, and an partial healing with predominantly type I collagen in 7 of
up to 90% reduction in the bursal-sided defect on 10 rabbits.
follow-up MRI. This study was limited by the small There are multiple other avenues that attempt to
patient population (20 patients) and lack of a control manipulate the local stem cell environment but require
group. Nonetheless, the possibility of inducing neo- further research before clinical application. These include
tissue formation in a partial rotator cuff defect without manipulation of local angiocrine factors produced by tis-
surgery is promising. sue-specific endothelial cells, induced pluripotent stem
Kim et al50 investigated clinical and MRI outcomes cells, and gene therapy approaches. At this point, these
following rotator cuff repair augmented with adipose- therapies are considered experimental, with minimal to no
derived MSCs loaded in fibrin glue. In their study, 35 clinical data to support their use.
patients received MSC injections and were compared with
35 matched control patients who did not receive
injections. At 2 years postoperatively, both groups Conclusions
significantly improved compared with preoperative levels, Cell therapy represents a promising approach for the
but there was no difference in clinical outcomes between treatment of symptoms associated with shoulder impinge-
the groups at 2 years, including pain, range of motion, and ment, rotator cuff tears, and glenohumeral OA. Further-
functional outcome scores. A significantly lower rate of more, there is emerging evidence of the potential for
failed healing in the MSC group (14.3%) compared with clinically meaningful tissue regeneration and healing.
2048 J.B. Carr II, S.A. Rodeo

patients as early as 3 months postoperatively. This tissue

Further basic science and clinical evidence is needed to
matured over time and became indistinguishable from
define the role of cell therapy in treating various muscu-
normal rotator cuff tissue on MRI, with complete healing in
loskeletal pathologies. Physicians should continue to use
7 of 12 patients. No tear progression was seen in any pa-
discretion when considering the use of cell therapy, and
tient, and clinical scores were improved in all patients at 2-
special attention should be given to preparation methods
year follow-up.
that ensure compliance with ethical and legal standards.

Other options to manipulate biology in Conclusion

shoulder
The landscape of biologic agents in orthopedic surgery
There are a variety of other biologic and nonbiologic ap- is rapidly changing. Physicians must maintain a thor-
proaches that are readily available and can also be useful in ough understanding of the growing literature to identify
the management of shoulder pathology. Pharmacologic the optimal indications for use of various biologic
therapy that maximizes a patient’s ability to heal must be agents, as such evidence can help guide clinical decision
considered depending on the patient’s medical making. Autologous biologic agents vary in ease of
comorbidities. For example, orthopedic surgeons should acquisition, in composition, and likely in effectiveness
focus on identifying and optimizing factors with known for treating a variety of shoulder pathologies. PRP is
negative effects on rotator cuff healing prior to surgical relatively easy to harvest, with heterogeneous clinical
management of a rotator cuff tear. Poor glucose control, results despite strong basic science support for its use.
osteoporosis, hypercholesterolemia, vitamin D deficiency, Cell therapy approaches, including use of BMAC and
smoking, and the use of nonsteroidal anti-inflammatory adipose-derived cells, also have promising basic science
drugs have all been associated with impaired rotator cuff evidence but few clinical studies to support their regular
healing.2,6,13,15,16,18,82,96 Every effort should be made to use. A critical limitation currently is the inability to
manage and reduce these risk factors prior to primary or isolate and expand via cell culture the very small number
revision rotator cuff repair. A primary care physician or of ‘‘stem cells’’ found in these various autologous
endocrinologist can be especially helpful in the manage- preparations. It appears that implanted cells act via a
ment of diabetes mellitus, osteoporosis, and smoking paracrine mechanism whereby they produce soluble
cessation. Sometimes pharmacologic intervention can be factors that stimulate local host cells, suggesting the
beneficial, especially in the management of hyperglycemia possibility of harnessing the small population of intrinsic
or poor bone mineral density. For example, hyperglycemia progenitor cells that are resident in many tissues. Finally,
has been shown to be detrimental to rotator cuff healing in a physicians should not neglect nonbiologic agents when
rat model.6 Certain medications, such as vitamin D and treating patients with shoulder pathology.
recombinant parathyroid hormone, have also been shown to Above all else, orthopedic surgeons must be well
have a positive effect on rotator cuff healing in preclinical informed when discussing biologic agents with patients.
studies.2,34 Similarly, low-intensity pulsed ultrasound has The combination of aggressive marketing and patient
been shown to improve the histologic appearance of rotator demand has led to the indiscriminate use of cell therapy
cuff tendon-bone integration and increase bone mineral for a wide range of musculoskeletal conditions in the
density at the cuff insertion site.61 United States. It is paramount that orthopedic surgeons
Another approach to healing augmentation is the use of provide leadership in this area and work
extracellular matrix materials (commonly referred to as a toward developing practice guidelines and policies for
‘‘patch’’) as a scaffold to support tendon healing. These the use of biologic agents. A rigorous approach to the
patches have been advocated for use in managing partial- use of ‘‘regenerative medicine’’ therapies and the
thickness rotator cuff tears and augmentation of large, full- maintenance of high clinical and research standards are
thickness rotator cuff repairs. There are 2 proposed required to move the field forward.
biomechanical mechanisms for improvement in healing.
First, the patch may act as a load-sharing device that can
help reduce peak strains across a partial rotator cuff defect
or a repaired tendon. Second, the patch may serve as a Disclaimer
scaffold to support cell attachment and new matrix syn-
The authors, their immediate families, and any research
thesis. An extracellular matrix patch may facilitate new
foundations with which they are affiliated have not
tissue formation by providing a supportive scaffold.8,90 A
received any financial payments or other benefits from
study by Bokor et al8 reported 2-year outcome results in 12
any commercial entity related to the subject of this
patients with partial rotator cuff tears treated with collagen
article.
patch augmentation. New tissue formation was seen in all
Biologic agents and shoulder pathology 2049

electrophysiological, biomechanical, and histological analyses. Am J

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