Platelet-Rich Plasma for Degenerative Spine Disease: A Brief Overview

Abstract

Background

The emergence of novel minimally invasive techniques has opened new horizons for the management of degenerative diseases of the spine. Platelet-rich plasma (PRP) has gained considerable attention through its applications in various pathologies. In the present review, an overview of the science behind the application of PRP is provided, ultimately focusing on the clinical trials that may render it a useful tool in the hands of spine surgeons in the future.

Methods

A review of the available literature is conducted, focusing on its existing clinical and experimental applications with a particular interest in the degenerative diseases of the spine.

Results

In terms of the degenerative diseases of the spine, initial studies suggest that it is a safe and effective method that could change the practice of spinal cord medicine in the years to come. The available studies demonstrate that besides being minimally invasive, causing less discomfort than that of surgery, it provides longer lasting improvement than standard pharmaceutical interventions.

Conclusions

PRP is an emerging and promising biodrug for the treatment of patients with spinal pain. PRP has demonstrated some promising qualities; however, careful consideration of its indications of use and strict protocols of application need to be established before widespread clinical induction.

1.Introduction

Degenerative diseases of the spine are a major cause of severe disability, workplace absence, and most importantly, loss of quality of life^1-3). They have been associated with stress on the spinal cord from frequent weight lifting, a confirmed history of cigarette smoking, prior trauma, frequent diving from a board, and participation in collision sports^4,5).

As far as the cervical spine is concerned, for both sexes, the mean age of diagnosis was set in the fifth decade of life (47.6 years for men and 48.2 years for women). However, men present a higher prevalence with 107.3 cases per 100,000 persons than women (prevalence: 63.5 per 100,000)⁶⁾. The vast majority of the cases present at the C5-C6 and C6-C7 levels^4,7) most likely because of their high mobility and increased weight load⁸⁾. Conversely, cervical myelopathy has an estimated prevalence of approximately 60.5 per 100,000⁹⁾. However, with the prevalence of neck pain increasing over the last two decades¹⁰⁾ and the application of advanced imaging techniques, such as MRI, increasing steadily as they become more readily available¹¹⁾, it is expected that the potential candidates for surgical management will increase in the years to come.

At the other end of the spinal cord, regardless of etiology, low back pain is estimated to have a point prevalence of 12% and a lifetime prevalence as high as 40%¹²⁾. Nevertheless, there is a high discrepancy among the available studies, with a reported incidence ranging from 1.5% to 36% and a point prevalence between 8.4% and 39.2%¹³⁾.

A plethora of factors may cause low back pain. Probably the most common factors are degenerative disk disease (DDD) and facet joint syndrome (FJS), whereas for the vast majority of patients, their symptoms are of unknown etiology¹⁴⁾. Occupational, lifestyle (such as obesity and smoking), and even psychological factors have all demonstrated a strong correlation with the pathogenesis of low back pain¹²⁾.

Keeping in mind the socioeconomic impact of this condition, the need for a definitive treatment is imperative. So far, pharmacological agents, physiotherapy, and lifestyle modifications have been employed either individually or in combination to manage spinal pain¹⁵⁾. In spite of the abundance of treatment protocols, none has currently provided evidence to be a universally safe and effective option¹⁶⁾.

Of the novel approaches that are currently under investigation, regenerative medicine shows great potential by making giant leaps forward over the past few years in various medical specialties. Extensive research on this domain is being carried out to identify novel factors that are not only more effective but also safer than the conventional ones. One agent that may possess a potent therapeutic potential in the management of degenerative spine diseases is platelet-rich plasma (PRP).

2.Background of the Technology

Furthermore, PRP is derived from whole blood centrifugation. The end product is a platelet hyperconcentrate of plasma that depending on its fibrin architecture cell content, is broadly categorized into four groups (Table 1)¹⁷⁾. Thus, it is characterized as a minimally manipulated, autologous blood product according to the Food and Drug Administration. As there is no standard protocol for the preparation of PRP¹⁸⁾, a variable concentration of thrombocytes has been used in clinical and research applications, ranging from 200 × 10³ to 120 × 10^{4 19-21)} platelets per μL, and their normal whole blood concentration ranges from 150 × 10³ to 350 × 10³ platelets/μL.

Table 1.

Classification of PRP Solutions.

Classification	Description
Pure platelet-rich plasma (P-PRP)	Platelets only in a low-density fibrin network
Leukocyte and platelet-rich plasma (L-PRP)	Leukocytes and platelets in a low-density fibrin network
Leukocyte and platelet-rich fibrin (L-PRF)	Leukocytes and platelets in a high-density fibrin network
Pure platelet-rich fibrin (P-PRF)	Platelets only in a high-density fibrin network

In spite of the fact that several preparation systems for PRP production currently exist^21-23), with different requirements for blood and activator inputs and variable yields in PRP volume and final platelet, leukocyte, and fibrinogen concentrations, the overall technique is fairly standard. Following the acquisition of an amount of peripheral blood in a tube containing an anticoagulant factor, the sample is centrifuged either once or twice to obtain the desired concentrations of cells²⁴⁾. This is conducted by collecting the so-called “buffy coat,” which contains the leucocytes, as well as the overlying plasma layer, which is rich in thrombocytes, because the erythrocytes sink to the bottom of the tube because of their higher density^22,25). Following that step, the platelets may be submitted to an additional stage of processing through the addition of activating factors, such as calcium chloride or thrombin. The latter induces degranulation of platelets and release of growth factors²⁶⁾. Finally, PRP is injected under local anesthesia at the site of interest following proper draping and following standard sterile techniques (Fig. 1)²⁷⁾. Following the intervention, the patient is instructed to avoid extensive and unnecessary mobilization of the injection site for 24 h^27,28).

Figure 1.

Schematic of the main steps of PRP preparation.

3.Physiology of PRP

Following injection, platelets have an expected life span of 8-10 days, throughout which small amounts of growth factors are produced²⁶⁾. The role of the activating factor is to enhance this production and hasten their release^26,29). The growth factors that have been identified are presented in Table 2. An extensive discussion on the physiology of thrombocytes and of the several bioactive proteins released by platelets is beyond the scope of the present article. Therefore, it is recommended that the interested reader refers to other articles for a more in depth presentation of the topic^30,31).

Table 2.

List of Most Clinically Relevant Proteins Contained in α-granules.

Protein	Role
Epidermal growth factor (EGF)	Proliferation and migration of endothelial cells, keratinocytes, and fibroblasts
Fibroblast growth factor (FGF)	Regeneration of soft tissue, bone, and nerve tissues
Insulin-like growth factor (IGF-I, IGF-II)	Glucose and amino acid metabolism, skeletal development
Vascular endothelial growth factor (VEGF)	Angiogenesis, leukocyte mobilization, and adhesion
Platelet-derived growth factor (PDGF)	Activator of fibroblasts, development of the bone, lungs, testis, skin, blood vessels, kidneys, glial cells, gastrointestinal tract
Transforming growth factor-β (TGF-β)	Tissue growth, repair, inflammatory responses, and angiogenesis

Besides their role in hemostasis, platelets are also involved in the generation and promotion of immune responses³²⁾. At a cellular level, each platelet contains a number of vesicles that contain several bioactive substances. These vesicles are distinguished into α-granules, dense granules, and lysosomes, in decreasing order of frequency³⁰⁾. Although dense granules are involved in hemostasis and inflammatory response and lysosomes are considered important for endosomal digestion, the role of α-granules is considered more complex as they contain factors that promote coagulation, inflammation, wound repair, cell adhesion, and mitogenesis^30,33,34).

Besides platelets, PRP has been found to contain several plasma proteins important for the regeneration of damaged connective tissue^35,36). Of the over 280 different proteins contained in α-granules³⁷⁾, probably the most clinically relevant ones for the present case are epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF-I and IGF-II), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β), along with a number of chemokines^25,26). These factors are stored and released in a selective manner upon the activation of the platelet³⁸⁾. Then, through a tightly regulated mechanism, the granules are fused with the plasma membrane and their content is exocytosed^33,34).

In particular, EGF induces the activity, proliferation, and migration of endothelial cells, keratinocytes, and fibroblasts, thus inducing tissue regeneration and wound healing^39,40). As its receptor (EGFR) is expressed virtually in all systems⁴¹⁾, extensive research is currently being conducted, with EGF being under investigation as an adjuvant for the treatment of nonhealing wounds⁴²⁾ and for its role in oncogenesis⁴³⁾.

Additionally, FGF is a group of 22 proteins that are responsible for the proliferation of fibroblasts⁴⁴⁾. Regeneration of bone and soft tissue is among the identified functions of FGF, as is organogenesis during the embryonic period⁴⁵⁾. Similarly to EGF, deregulation of its signaling has been associated with oncogenesis and tumor proliferation⁴⁶⁾.

Another key protein contained in α-granules is insulin-like growth factor (IGF-I and IGF-II), which is primarily involved in glucose and amino acid metabolism^47,48). In addition, growth retardation in rats deficient in IGF-I and II^49,50) has led to the conclusion that this protein is important for skeletal development, inducing bone and cartilage formation and repair^51,52). IGF-I is also involved in the differentiation and growth of neurons, oligodendrocytes⁵³⁾, arterial cells^54,55), and the follicles in ovaries⁵⁶⁾.

As the name implies, VEGF is involved primarily in angiogenesis. Each of the seven members of the family is expressed in specific organs already from fetal life⁵⁷⁾. Besides their key role in development, VEGFs also induce leukocyte mobilization and adhesion at the site of wound healing^57,58).

Further, PDGF is considered a potent activator of fibroblasts, mesenchymal cells, and glial cells and is involved in the development of the bone, lungs, testis, skin, and blood vessels, among others^59,60).

Lastly, transforming growth factor-β (TGF-β), similarly to the aforementioned, has a central role in tissue growth and repair, inflammatory responses, and angiogenesis^61,62). At a cellular level, TGF-β controls differentiation and apoptosis⁶²⁾ and possesses a central role in wound healing⁶³⁾.

Exercise may have an impact on the end concentration of growth factors⁶⁴⁾ or platelets⁶⁵⁾ in PRP. Interestingly, increased concentrations of some cytokines have been found in PRP obtained from male patients, and the same applies for that coming from younger patients⁶⁶⁾. Furthermore, individual parameters are speculated to have an impact on the effectiveness of PRP due to their immediate effects on its contents. These include whole blood platelet count, blood pressure, diet, and mental stress⁶⁷⁾. As a result, the need for a standardization of the production process of PRP in every aspect has been underlined¹⁸⁾.

4.Medical Applications of PRP

Furthermore, PRP has been successfully applied for the treatment of osteoarthritis¹⁶⁾, tendinopathy⁶⁸⁾, alopecia⁶⁹⁾, and skin rejuvenation⁷⁰⁾, to name a few. At the same time, its effects on erectile dysfunction⁷¹⁾, reproductive medicine⁷²⁾, and regenerative dentistry⁷³⁾ are under investigation (Table 3).

Table 3.

PRP is Currently Applied by a Variety of Medical Specialties or is under Investigation for the Nonoperative Management of a Number of Conditions That are Constantly Increasing.

Orthopedics	Dermatology
Hip osteoarthritis	Alopecia
Knee osteoarthritis	Skin rejuvenation/restoration
Epicondylitis	Reproductive medicine
Plantar fasciitis	Poor ovarian reserve
Achilles’ tendinopathy	Thin endometrium
Patellar tendinopathy	Erectile dysfunction
Anterior cruciate ligament reconstruction	Dentistry
Talar osteochondritis dissecans	Regenerative dentistry
DDD	Ophthalmology
FJD	Chorioretinopathy
Fracture healing	Neurosciences
Endocrinology	Neurodegeneration
Diabetes	ENT
	Tympanic membrane perforation

In orthopedics in particular, PRP has been investigated for its potential therapeutic effects for epicondylitis, plantar fasciitis, Achilles' and patellar tendinopathy, hip and knee osteoarthritis, anterior cruciate ligament reconstruction, and talar osteochondritis dissecans¹⁸⁾.

Previous studies have found a significant effect of PRP therapy in the management of pain and joint function²⁸⁾. The beneficial effect for knee osteoarthritis pain relief is reported to last for at least 12 months and as long as 2 years from the initiation of the treatment^28,74). Intra-articular injections of PRP have been shown to be as effective as hyaluronic acid in the improvement of quality of life in patients with knee osteoarthritis⁷⁵⁾. Nevertheless, the effects for Achilles' tendinopathy, if present, are considered only short term⁷⁶⁾. The exact opposite were the conclusions of Li et al. for the case of epicondylitis⁷⁷⁾. According to their meta-analysis, corticosteroids provide a more potent immediate effect, yet PRP provides a longer lasting improvement in the quality of life.

Aesthetic dermatology has proven to be a fertile ground for the application of PRP, with hair and dermal augmentation, skin restoration, and rejuvenation being the areas where extensive research is being conducted and the ones with some of the most impressive clinical outcomes⁷⁸⁾. In particular, as far as the former is concerned, a systematic review demonstrated a statistically significant difference in hair density between PRP and placebo groups⁶⁹⁾, and according to another one, PRP is as effective as other pharmaceutical interventions (e.g., finasteride and minoxidil) but with less potential side effects⁷⁹⁾. These results render PRP a promising alternative to chronic medication intake.

Importantly, using the patient's own blood, PRP is considered to have a high safety profile as the risk for allergic reactions, rejection, or graft-versus-host disease is virtually nonexistent^80,81). Still, some minor adverse effects have been documented, primarily related to the injection process. These include local skin infection and irritation⁸²⁾, pain at the injection site⁸³⁾, and very rarely, hypersensitivity reactions associated with the substances used for the preparation of PRP⁸⁴⁾.

5.Pathophysiology of Degenerative Spine Disease

The primary hypothesis regarding the pathophysiology of DDD is dominated by the wear and tear principle. It is hypothesized that this condition reflects an accelerated aging process⁸⁵⁾ with progressive loss of notochord-derived cells that are abundant in juvenile disks^86,87). These cells are essential for the homeostasis of the nucleus pulposus^88,89). Proteoglycans and collagen are the main constituents of the nucleus pulposus and are produced by chondrocytes⁹⁰⁾. Following the fate of their cells of origin, proteoglycans reach a peak during adolescence and decrease thereafter^91,92). The most abundant proteoglycan is aggrecan, the loss of which is associated with a decreased ability of the intervertebral disk to bear the loading forces and ultimately leads to loss of height and bulging of the disk⁹³⁾. Similarly, the cell population of the annulus fibrosus undergoes remarkable changes even in the absence of external loading⁹⁴⁾. Facet joints are not independent of the condition of the intervertebral disks, but rather, their function is affected in the presence of disks of decreased height⁹⁵⁾.

The question concerning the regulation of the metabolism of intervertebral disks still holds as the process is fairly complicated. A number of proteins appear to be involved in their homeostasis, with each one holding multiple roles (Fig. 2). To begin with, EGF has been found to inhibit aggrecan production⁹⁶⁾ and induce cartilage matrix turnover⁹⁷⁾ and inflammatory response⁹⁸⁾. FGF arrests chondrocyte proliferation^99,100) and downregulates aggrecan synthesis¹⁰¹⁾ and the activity of aggrecanase¹⁰²⁾, the enzyme responsible for the catabolism of aggrecan. Conversely, IGF-1 induces chondrocyte proliferation and survival in vitro¹⁰³⁾, aggrecan formation¹⁰⁴⁾, and overall disk cell survival¹⁰⁵⁾. The release of VEGF by chondrocytes leads to neovascularization^106,107) and the inhibition of aggrecan synthesis¹⁰⁸⁾. The same effect on the blood supply to the disk appears to have been caused by the release of PDGF¹⁰⁹⁾, which also induces aggrecan incorporation into the extracellular matrix of chondrocytes, playing a key role in cartilage repair¹¹⁰⁾. Finally, TGF-β is essential for collagen and aggrecan formation^111,112).

Figure 2.

Major proteins involved in intervertebral disk homeostasis.

Through preclinical studies, it has been hypothesized that the proteins contained in PRP enhance the proliferation and differentiation of the nucleus pulposus¹¹³⁾ and reduce inflammation¹¹⁴⁾ and subsequently disk degeneration. In addition, PRP may possess angiogenic effects that could stimulate axonal regeneration following injury¹¹⁵⁾. On the basis of these promising results, PRP has been introduced in clinical research particularly for the treatment of DDD and as an adjuvant in spinal fusion and management of spinal cord injury, which will be the topic of the following section.

6.PRP and Spine

So far, intradiscal (Fig. 3a, b) and intra-articular (Fig. 3c) injection of PRP for DDD and FJS, respectively, have been described. Lutz reported improvement in low back pain and range of motion in a patient with DDD and Modic I changes in MRI following PRP treatment¹¹⁶⁾. Besides clinical improvement, a radiological one was noted as well, with an increase in T2 signal intensity of the affected disk¹¹⁶⁾ (Fig. 4) and reversal of Modic I changes, which lasted 1 year after the intervention. In another study, no statistically significant difference was found in 1-year postinterventional MRI in spite of an otherwise significant clinical improvement¹¹⁷⁾.

Figure 3.

Illustrative cases of PRP injection in two different patients with DDD (b) and FJS (c). Following proper draping and localization of the regions of interest, a paramedian approach is followed (a). The needle is inserted under continuous fluoroscopy at the PRP injection sites. Intraoperative anteroposterior view of intradiscal injection of PRP at the L3/L4 and L4/L5 levels (b) and in the articular facets of L4/L5 bilaterally (c).

Figure 4.

Reversal of disk degeneration has been reported following intradiscal injection of PRP. Schematic of a grade 4 DDD (a) according to the Pfirrmann grading system regressing to a grade 3 degeneration (b).

In a series of 22 patients most of whom demonstrated evidence of DDD in the lower lumber spine, a single injection of autologous PRP led to an improvement by over 50% in almost half of the participants, over a follow-up period of 6 months¹¹⁸⁾. No complications were observed; nevertheless, some patients experienced worsening of their symptoms during follow-up.

To the best of the authors' knowledge, Cheng et al. provided the longest follow-up to date¹¹⁹⁾. One of three patients reported no difference in symptoms, and the remaining 69% demonstrated improvement, irrespective of the demographic profile of the patient (i.e., sex and age) and of the number of levels treated.

In a recent meta-analysis of the studies investigating the effectiveness of PRP in lumbar disk degenerative disease, a statistically significant improvement of the quality of life as measured using the visual analog scale was found¹²⁰⁾. The authors concluded that the technique is not only potentially effective but also safe, with only two cases of intermittent paresthesia lasting for less than 7 days reported¹¹⁷⁾.

Clinical studies on the effectiveness of PRP in the management of FJS have also been conducted. Wu et al. achieved a statistically significant decrease in pain at rest and during movement within 3 months after treatment in 19 patients¹²¹⁾. No complications were documented, and four patients experienced intermittent aggravation immediately following the injection. In another study conducted by the same group, intra-articular local anesthetic and corticosteroid injection provided more potent immediate effects than PRP; however, at 3 and 6 months follow-up, the effects in the PRP group were more prominent¹²²⁾.

At a preclinical level, PRP has been investigated as a potential inducer of spinal fusion¹²³⁾. As the available data are still inconclusive regarding the potential superiority of PRP over best clinical practice, more studies are needed in the years to come. Nevertheless, at a clinical setting, PRP and autograft bone chip induced higher fusion rates than those of the latter alone¹²⁴⁾. Recently, a meta-analysis suggested that fusion rate is unaffected by the addition of PRP, yet improvement of back pain and faster bone union can be achieved¹²⁵⁾. These results are challenged by another meta-analysis that found no difference in quality of life but lower chance of successful fusion with PRP¹²⁶⁾. Finally, improved new bone formation was the main finding of the meta-analysis by Manini et al.¹²⁷⁾.

At a preclinical setting, PRP has also been studied as an adjunct in interbody fusion in the cervical spine but without any clinical significance¹²⁸⁾. Lam et al. provided a case report of the treatment of cervical pain 3 weeks after ultrasound-guided intradiscal injection of PRP¹²⁹⁾.

Heterotopic ossification is a common complication of PRP treatment, which can be found in as many as 40% of patients receiving PRP for core muscle injury¹³⁰⁾. Even though, to the best of our knowledge, this complication has not been explicitly investigated to date, PRP as an adjuvant in spinal fusion did not result in better fusion rates¹³¹⁾.

The most promising application of PRP is that following spinal cord injury. Preliminary studies with short-term follow-up provide evidence of a potentially beneficial effect both in animal models¹¹⁵⁾ and in the rehabilitation of patients¹³²⁾.

At the time of peer reviewing of the present article, a systematic review by Kawabata et al. was published³¹⁾. In their work, the authors identified 13 clinical studies with a total of 326 patients who received intradiscal PRP therapy. In 10 of these studies, the authors reported a statistically significant clinical improvement in a follow-up period that lasted from 6 months up to 6.5 years. It is worth mentioning that the remaining three studies that only showed a trend toward improvement had recruited either one or two participants. A summary of the clinical studies discussed herein is provided in Table 4.

Table 4.

List of the Included Studies Reporting the Clinical Applications of PRP in Degenerative Spine Disease.

Author (Year)	Disease	N of subjects	Outcomes	Follow-up
Wu et al. (2016)	FJS	19	VAS, ODI, RDQ, mMN	3 months
Wu et al. (2017)	FJS	41 (21 PRP, 20 controls)	VAS, ODI, RDQ, mMN	6 months
Levi et al. (2016)	LDDD	22	VAS, ODI	6 months
Akeda et al. (2017)	LDDD	14	VAS, RDQ, X-ray, MRI	10 months
Lutz (2017)	LDDD	1	MRI	12 months
Cheng (2019)	LDDD	29	NRS, SF-36	6.57 years
Kubota (2019)	LDS	62 (31 PRP, 31 controls)	VAS, BFR	24 months
Lam and Hung (2020)	CDDD	1	VAS, NDI, SPADI	3 weeks
Lutz et al. (2022)	LDDD	37	NASS patient satisfaction index	18 months

CDDD, cervical degenerative disk disease; LDDD, degenerative disk disease; LDS, lumbar degenerative spondylosis; BFR, bone fusion rate; mMN, modified MacNab criteria; MRI, magnetic resonance imaging; NASS, North American Spine Society; NDI, neck disability index; NRS, numeric rating scale; ODI, Oswestry disability index; RDQ, Roland–Morris Disability Questionnaire; SF-36, MOS Short-Form 36-Item Health Survey; SPADI, shoulder pain and disability index; VAS, visual analog scale

7.Future Perspectives

Being at its early stages of development, lack of consensus exists regarding the details of the therapeutic protocol. Levi et al. administered 1.5 mL of PRP, along with another 1.5 mL of contrast solution, gentamycin, and lidocaine¹¹⁸⁾, whereas Wu et al. injected 0.5 mL of PRP in the facet joint of interest¹²¹⁾, and Navani et al. injected approximately 2 mL intradiscally¹³³⁾.

In addition to this, some studies did not apply strict objective exclusion criteria with regard to the staging of the disease^118,133), whereas other groups^117,134) used indices such as the Pfirrmann grade to categorize their patients according to the severity of the disk degeneration. Similarly, in some studies, no differentiation according to the etiology of the symptoms was made (DDD vs FJD)¹³⁵⁾. It is more likely that patients managed at the earlier stages of the disease will benefit more than those with profound compression of nerve tissue. The level at which PRP could arrest the progression of DDD or FJS needs to be proven.

Another point in need of consensus is the level of improvement that is considered clinically meaningful. Besides the confusion caused by the different grading scales in use, for a subjective measurement such as pain, the level at which an intervention was deemed successful differs among groups, with some adopting a more conservative approach and others a more optimistic one.

Lastly, as it was mentioned earlier, individual differences may be responsible for the different qualities of the end product. It is a possibility, therefore, that PRP could prove to be helpful for only a subgroup of the patients with DDD. Even then, the provision of a tailored treatment could lead to ground changing results in modern spinal cord medicine.

Limitations

The present narrative review is not free of limitations. To begin with, as the technique discussed is still at its infancy with regard to potential applications in the spine, the available literature is limited and conclusions could not be generalized. In addition, the study design cannot allow for comparison among studies and analysis of data, for which a systematic review and meta-analysis is warranted. In the same sense, even though all efforts have been made to include as many studies as possible and to provide all aspects and views, a narrative review lacks scientific power of a systematic one.

8.Conclusion

PRP is an emerging and promising biogrug for the treatment of patients with spinal pain. Although its application is at its infancy, some very important conclusions have been drawn, which drive intensive and extensive research in the domain.

PRP has demonstrated some promising qualities, but by no means, it should be welcomed as a panacea. Careful consideration of its indications of use and strict protocols of application need to be established before widespread clinical induction. It is expected that in the years to come, multidisciplinary approaches will aid in the deeper understanding of the underlying processes of soft tissue and bone regeneration. Nevertheless, until the day arrives for it to be incorporated in everyday practice, the burdens of proper patient selection and optimal dosage administration need to be addressed first. As such, having established a highly safe profile, more clinical trials addressing these key parameters are required.

Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.

Sources of Funding: None

Author Contributions: SA collected the data and drafted and approved the manuscript; SK conceived and approved the manuscript.

Ethical Approval: Ethical approval was waived by the ethics committee because this study is a narrative review.

Informed Consent: Informed consent was obtained for the use of the material published herein.