Rotator cuff injuries are a common source of shoulder pathology and result in an important decrease in quality of patient life. Given the frequency of these injuries, as well as the relatively poor result of surgical intervention, it is not surprising that new and innovative strategies like tissue engineering have become more appealing. Tissue-engineering strategies involve the use of cells and/or bioactive factors to promote tendon regeneration via natural processes. The ability of numerous growth factors to affect tendon healing has been extensively analyzed
Rotator cuff lesions represent the vast majority of shoulder injuries in adult patients and are a common contributing factor to shoulder pain and occupational disability.
The incidence of this condition is increasing along with an aging population [
Improvements in arthroscopic instrumentation and suture anchor technology have allowed the development of stronger constructs with multiple suture configurations, allowing repair of large and massive tears through minimally invasive means. However, although repair instrumentation and techniques have improved, healing rates have not. A high failure rate remains for large and massive rotator cuff tears [
A recent meta-analysis has shown that the development and introduction of novel surgical techniques are not related to an improvement of clinical and anatomical results over the investigated period (1980–2012) [
To enhance tendon tissue regeneration, new biological solutions including growth factors, platelet-rich plasma (PRP), and stem cells are being investigated.
This review will outline the current evidence for the novel frontier in the management of rotator cuff disease including growth factor and stem cell therapy.
Growth factors are signal molecules involved in the control of cell growth and differentiation and are active in different phases of inflammation. They are produced by inflammatory cells, platelets, and fibroblasts.
Rotator cuff healing occurs via a sequence of inflammation, repair, and remodeling [
Because rotator cuff healing results in reactive scar formation rather than a histologically normal insertion site, addition of these factors may enhance the repair-site biology.
PDGF is a basic protein composed of two subunits, an A and a B chain, that exists in three main isoforms (PDGF-AA, PDGF-BB, and PDGF-AB). These isoforms function as chemotactic agents for inflammatory cells and help to increase type I collagen synthesis and induce TGF-
Several studies have examined the role of PDGF as a mitogenic and chemotactic cytokine that can enhance tendon and ligament healing.
Uggen et al. [
A similar study used an interpositional graft composed of a type I collagen matrix, enriched with recombinant human PDGF-BB (rhPDGF-BB), implanted in an ovine model for rotator cuff repair [
TGF-
Of the three isoforms, TGF-
Kim et al. [
A subsequent study by the same group using a heparin-/fibrin-based TGF-
The use of PRP as a biological solution to improve rotator cuff tendon healing has gained popularity over the last several years.
PRP is a whole blood fraction containing high platelet concentrations that, once activated, provides a release of various growth factors which participate in tissue repair processes [
PRP not only inhibits the inflammatory effects of interleukin 1
There are several different PRP formulations currently available. PRP can be classified into four main categories: pure PRP (P-PRP), leucocyte-rich PRP (L-PRP), pure platelet-rich fibrin (P-PRF), and leucocyte-rich platelet-rich fibrin (L-PRF). In each category, platelet concentration can be obtained by different processes, either in a fully automatized setup or by manual protocols [
Among PRP formulations, a further division can be made between those which are activated
The role of leucocytes in PRP is a controversial issue in the literature.
Basic science studies showed that growth factors and cytokine concentrations are influenced by the cellular composition of PRP, with leukocytes increasing catabolic signaling molecules [
Furthermore L-PRP has been found more proinflammatory when injected in rabbits [
Most clinical studies have used numerous different PRP formulations. The obtained results have never been analyzed using the leucocyte content of the final concentrate as a key parameter. Thus, differences between P-PRP and L-PRP preparations are still unknown.
However the leukocyte content does not seem to induce negative effects or to impair the potentially beneficial effects of PRP and no uncontrolled immune reactions of L-PRPs have been also reported; on the contrary, the use of L-PRP could diminish pain and inflammation of the treated sites [
Literature showed that PRP can be applied either by direct injection or by application of a PRP matrix scaffold on repaired tissues. The main characteristics of controlled clinical studies using PRP in arthroscopic rotator cuff repair are reported in Table
Controlled clinical studies investigating the use of PRP in rotator cuff lesions.
Surgical use of PRP in arthroscopic rotator cuff repair | |||||
---|---|---|---|---|---|
Author | Evidence | PRP formulation | Surgical technique | Number of patients | Comments |
Randelli et al. |
Level 1 |
Injectable PRP |
Single row | 53 | Better clinical outcomes at 3 mo; better clinical outcomes at 12, 24 months for smaller tears with PRP |
Ruiz-Moneo et al. |
Level 1 |
Injectable PRP |
Double row | 63 | No differences in rotator cuff healing or function at 1 year |
Antuña et al. |
Level 2 |
Injectable PRP |
Single row | 28 | No differences in clinical outcomes and healing rate at 2 years |
Charousset et al. |
Level 3 |
Injectable PRP |
Double row | 70 | No differences in cuff healing or function at 2 years |
Gumina et al. |
Level 1 |
Suturable PRP |
Single row | 76 | Lower retear in the PRP group; no differences for clinical outcomes |
Jo et al. |
Level 2 |
Suturable PRP |
Transosseous equivalent | 42 | Trend for lower re-tearing in the PRP group; no differences for recovery and function |
Jo et al. |
Level 1 |
Suturable PRP |
Transosseous equivalent | 48 | Lower retear and function at 1 year in the PRP group |
Zumstein et al. |
Level 1 |
Suturable PRP |
Transosseous equivalent | 20 | Increased vascularization for cuff tears with PRP |
Castricini et al. |
Level 1 |
Suturable PRP |
Double row | 88 | No difference for clinical outcomes at 16 months; better restoration of footprint in PRP group |
Rodeo et al. |
Level 2 |
Suturable PRP |
Single OR double row/transosseous equivalent | 67 | No difference in tendon healing, tendon vascularity, and clinical scores at 1 year |
Barber et al. |
Level 3 |
Suturable PRP |
Single row | 40 | Lower retear in the PRP group; better healing for smaller tears with PRP |
Bergeson et al. |
Level 3 |
Suturable PRP |
Single or double row | 37 | Higher retear rate in patients with at-risk rotator cuff tears with PRFM; no difference in functional outcome scores |
Weber et al. |
Level 1 |
Suturable PRP |
Single row | 60 | No difference in perioperative morbidity, clinical outcomes, or structural integrity |
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PRP injections for rotator cuff tendinopathy | |||||
Author | Evidence | PRP intervention | Control intervention | Number of patients | Comments |
|
|||||
Rha et al. |
Level 1 |
2 PRP (3 mL) injections at a 4-week interval | 2 dry needling procedures at a 4-week interval | 39 | PRP was superior with respect to pain, function, and range of motion over a 6-month period |
Kesikburun et al. |
Level 1 |
1 injection of PRP (5 mL) | 1 injection of saline solution (5 mL) | 40 | No difference for quality of life, pain, disability, and range of motion at 1 year |
Conflicting results on the effectiveness of PRP use in rotator cuff tendon repair were produced, making it now difficult to draw definitive conclusions.
The clinical studies published to date have different experimental designs with a level of evidence that varies from 1 to 4. Moreover, there are differences in PRP formulations in terms of growth factor concentration and catabolic enzyme content [
Experimental protocols present differences among the trials, concerning volume of autologous blood collected, speed and time of centrifugation, method of administration, activating agent, presence of leukocytes, final volume of PRP, and final concentration of platelets and growth factors. The surgical technique (transosseous equivalent, single, or double row) and the rehabilitation protocol (standard or rapid) were not the same among different studies.
In spite of the differences in surgical techniques, PRP formulation, size of the lesions, retear rate have been recalculated by combining the available data from studies in order to determine the role of PRP in improving the rotator cuff healing after surgical repair.
Differences in term of retear rate between PRP and control group were assessed by a chi-square test. The analysis of all studies examined showed that there was no significant difference in the retear rate between PRP and control group. The retear rate was 31% (101 out of 323) and 37% (115 out of 312), respectively (
A significant difference was found when a stratified analysis was performed to analyze the results of small and medium lesions of the rotator cuff. The rate of reinjury was 7.9% among patients treated with PRP, compared to 26.8% of those treated without PRP [
It is important to emphasize that, with the exception of two cases of infection, no complications have been reported from the use of PRP. Bergeson et al. [
Although clinical studies have produced conflicting results, data on PRP suggest a beneficial effect on healing process when applied during rotator cuff repair. The stratified analysis of small or medium lesions showed a significantly lower retear rate in the PRP group. Therefore, it currently seems that PRP may improve healing of arthroscopically repaired small and medium rotator cuff lesions, which appear more prone to a biological response to treatment with growth factors.
Further prospective randomized controlled trials (level 1 evidence) are necessary to define the role of PRP in healing of rotator cuff repair.
Injections of PRP have gained popularity in the treatment of tendinopathy because of their promoting effects on tendon cell proliferation, collagen synthesis, and vascularization, which have been shown in animal and
In spite of this popularity and increasing use in clinical settings we have found only two controlled randomized trials evaluating the use of PRP injections in rotator cuff tendinopathy [
These studies have reported controversial results on the effectiveness of the use of PRP injection in chronic rotator cuff tendon diseases.
The systems of PRP preparation were not the same among trials and different treatment protocols were used (single or double PRP injections). Furthermore, the presence of some bias including the concomitant standard exercise program and the needle stimulus effect can have influenced the results of studies. The nature of rotator cuff disease was also not the same throughout the studies and patients refractory to physical therapy and corticosteroid injection seem to have a benefit from the PRP use.
Extrinsic and intrinsic factors including anatomical problems, joint kinematics alterations, and age- and vascularity-related degenerative changes may play a role in developing such disease.
More studies with a high level of evidence are required to validate the role of PRP injections in the subacromial space for treatment of rotator cuff diseases.
Stem cells are defined as unspecialized cells with a self-renewal potential, which are able to differentiate into various adult cell types. The most common stem cell sources are embryonic and adult stem cells.
Embryonic stem cells are truly pluripotent; that is, they are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm.
In contrast to embryonic stem cells, multipotent adult stem cells are characterized by a differentiation potential restricted to tissues of 1 germ layer. Those which can differentiate into various forms of mesenchymal tissue (i.e., bone, tendon, cartilage, and muscle) are termed mesenchymal stem cells (MSCs).
Most of the clinical related stem cells research to date has focused on adult stem cells rather than embryonic stem cells, as the latter are associated with numerous regulatory and ethical constraints.
MSCs are progenitor cells that have the capacity to self-renew and differentiate into several different mesenchymal tissues including muscle, fat, bone, ligament, tendon, and cartilage [
Bone marrow is the main source of MSCs for rotator cuff healing and can be easily accessed by surgeons to harvest cells, the extraction and culture techniques of which, as well as the conditions for propagation, have been extensively defined. For these reasons, bone marrow-derived MSCs (BMSCs) may have valid clinical use, and there is evidence showing that BMSCs can be manipulated to differentiate into a tenogenic lineage and produce tendon tissue when exposed to the appropriate stimuli.
The iliac crest is the most common site for MSC harvesting, although a number of other sources have been recently identified. Recent research performed by Mazzocca et al. [
Beitzel et al. [
MSCs can also be collected from other sources, such as adipose tissue; this can be easily accessible although its cells have an apparently reduced ability to differentiate compared to BMSCs [
Tendon derived stem cells (TDSCs) are considered of extreme interest for rotator cuff repair enhancement. Existence of TDSCs has been first shown in murine patellar and human hamstring tendons by Bi et al. [
Recently, Song et al. [
The use of MSCs to enhance tendon regeneration has been examined in multiple animal models of tendon healing. MSC can be applied directly to the site of injury or can be delivered on a suitable carrier matrix, which functions as a scaffold while tissue repair takes place. In an attempt to augment tendon-bone healing in a rat rotator cuff repair model, Gulotta et al. [
Yokoya et al. [
Kim et al. [
Shen et al. [
Up to now, only one cohort study has evaluated the safety of clinical application of MSCs in shoulder surgery. In this study Gomes et al. [
Autologous BMMCs were harvested from the iliac crest prior to the surgical repair and subsequently injected into tendon borders after being fixed down by transosseous stitches. The BMMC fractions were obtained by cell sorting and resuspended in saline enriched with 10% autologous serum. Each patient was monitored for a minimum of 12 months, and University of California, Los Angeles (UCLA), scores improved on average from 12 to 31, and magnetic resonance imaging showed tendon integrity in all 14 patients. No control group was included in this study, but for this procedure, overall rates of rerupture during the first postoperative year range from 25% to 65%, depending on lesion diameter. Only 1 patient in the following year relapsed with loss of strength and pain. Unfortunately, only 14 patients were enrolled in this study, making it difficult to determine the efficacy of BMMCs as an adjunct to cuff repair at this time. However, these results suggest that BMMC therapy is a safe treatment that has potential to enhance tendon repair. Further research will be critical to better investigate the use of this biologic approach.
Several regenerative approaches have been investigated to augment tendon healing after arthroscopic cuff repair.
The ability of numerous growth factors to affect tendon healing has been extensively analyzed
Different delivery systems for these factors, including simple injection, coated sutures, fibrin sealants, heparin-fibrin delivery systems, collagen, and hyaluronic acid sponges, are being tested. PRP is a whole blood fraction which contains several growth factors. Different PRP formulations exist: leucocyte-poor and leucocyte-rich, activated and unactivated. Moreover, PRP can be administrated either with a simple injection or in a fibrin-matrix clot. Clinical trials using different autologous PRP formulations after rotator cuff tear repairs have provided controversial results.
However, favourable structural healing rates have been observed for surgical repair of small and medium rotator cuff tears.
Cell-based approaches have also been suggested to enhance tendon healing. Bone marrow is a well known source of MSCs; recently,
The authors declare that there is no conflict of interests regarding the publication of this paper.