Application of cord blood-derived platelet-rich plasma in the treatment of diseases

Abstract

Platelet-rich plasma (PRP), a blood product containing high concentrations of platelets, has been increasingly used for the treatment of a number of diseases because of its anti-inflammatory and regenerative properties. PRP is generally obtained from the patient’s own peripheral blood when used in clinical applications, but allogeneic PRP extracted from umbilical cord blood has also attracted attention due to its unique advantages. The main purpose of this narrative review was to summarize the research and clinical application of cord blood-derived PRP (CB-PRP) in the treatment of diseases up to April 2024. This review also discusses the differences between CB-PRP and autologous PRP (A-PRP). A thorough search of PubMed® and Clinicaltrials.gov identified 13 articles and four clinical trials. To date, CB-PRP has been primarily studied in the fields of orthopaedics, dermatology, neurology, obstetrics/gynaecology and ophthalmology. This is likely to be because this research is relatively novel. Considering the differences between the characteristics of A-PRP and CB-PRP, it is thought that CB-PRP might hold more promise for broader applications in the future.

Introduction

Platelet-rich plasma (PRP) is a preparation that is rich in platelets, fibrinogen, fibrin, chemokines and leukocytes with a platelet concentration of at least 1 000 000 platelets/μl, which is usually five-times higher than normal levels. ¹ PRP offers anti-inflammatory and regenerative properties through angiogenesis, cell differentiation and proliferation. ² Traditionally, PRP was mainly derived from adult peripheral blood and was used for the treatment of autologous diseases. Consequently, some literature reports considered it to be simply a blood product that was derived from the user's own body.^3–5 In practice, PRP can also be applied to allogeneic bodies. In recent years, PRP derived from cord blood (CB) has been employed in the allogenic treatment of some diseases and it has shown good therapeutic effects.^6–8 This might be because umbilical cord blood-derived PRP (CB-PRP) has potentially more growth factors and anti-inflammatory molecules compared with autologous PRP (A-PRP) derived from adult peripheral blood. ⁶

This narrative review primarily presents the current research status surrounding the application of CB-PRP in the treatment of different diseases. This review also discusses the differences between CB-PRP and A-PRP.

Methods

Data source and study selection

A literature search was performed to identify studies that focused on the use of CB-PRP for the treatment of diseases up to April 2024 using the following key terms: (“umbilical” OR “cord blood”) AND (“platelet-rich plasma” OR “PRP” OR “PRG”). PRG, short for platelet-rich gel, is the gel form of PRP. The databases that were searched were PubMed^® and Clinicaltrials.gov. The search strategy used in this narrative review involved a comprehensive exploration of the available studies on CB-PRP across authoritative literature and clinical trial databases, screening of representative research and analysing them based on the types of diseases treated using CB-PRP. This narrative review was conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA). ⁹ The search identified a total of 13 articles^{6–8,10–19} and four clinical trials (ClinicalTrials.gov ID NCT06302582, NCT05095597, NCT04636853 and NCT05706896) were considered eligible for inclusion in this narrative review.

Research on CB-PRP in bone and joint diseases

As is well documented, bone and joint diseases form a group of clinically heterogeneous diseases characterized by various bone strength disorders, bone structural defects and bone mass abnormalities. ²⁰ Bone and joint diseases are the fourth most widespread disease after cardiovascular disease, cancer and diabetes mellitus; and they severely impact the quality of life of patients. ²¹

A previous study enrolled 100 patients with hip osteoarthritis (OA) who were treated with three weekly ultrasound-guided injections of either CB-PRP or A-PRP. ⁶ An independent statistician, blinded to the study outcome, selected patients for a match-paired analysis. ⁶ Clinical evaluations were performed before the treatment and after 2, 6 and 12 months using the Harris Hip Score (HHS), the Western Ontario and McMaster Universities Osteoarthritis Index and Visual Analogue Scale (VAS) pain scores. ⁶ No major adverse events were recorded following CB-PRP injections. ⁶ Significant improvements in VAS (P = 0.031) and HHS (P = 0.011) were documented at 2 months for CB-PRP; and patients with a low OA grade (Tonnis 1–2) showed a significantly higher HHS improvement with CB-PRP than A-PRP at 12 months (P = 0.049). ⁶ These results suggest that the efficacy of CB-PRP was influenced by OA severity. CB-PRP showed more benefits when advanced OA cases were excluded from the analysis. ⁶

To investigate the role of intra-articular injections of CB-PRP for treating patients with knee OA in terms of safety and clinical outcomes, 25 patients with knee OA were treated with a single intra-articular knee injection of CB-PRP in a volume of 10 ml. ¹⁰ Follow-up was undertaken at 0, 4, 8, 12 weeks and 6 months after treatment, which evaluated clinical parameters and functional performance. ¹⁰ The results showed no serious adverse events were identified and CB-PRP generated reliable therapeutic effects. ¹⁰

A randomized controlled clinical trial evaluated 71 patients with mechanically stable nonunion who were treated weekly (for three consecutive weeks) with ultrasound-guided percutaneous injections of CB-PRP or A-PRP. ⁷ The primary outcome was healing (at 12 months) and the secondary outcomes were radiological evolution (at 2 and 6 months) and changes in pain intensity (at 6 months). ⁷ The results demonstrated that both CB-PRP and A-PRP decreased pain perception in patients with persistent nonunion. ⁷ Bone consolidation was assessed over time without significant differences between CB-PRP and A-PRP treatment. ⁷ Thus, CB-PRP appeared to be a valid alternative when specific clinical conditions suggested avoiding the use of A-PRP. ⁷

In terms of basic research, as early as 2011, a study established that CB-PRP promoted the proliferation and osteogenic differentiation of dental stem cells from human exfoliated deciduous teeth, dental pulp and periodontal ligament. ⁸ Meanwhile, another study found that cryopreserved CB-PRP induced the osteoblastic differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). ¹¹ These findings suggest that CB-PRP might play an important role in bone regenerative medicine.

Research on CB-PRP in spinal cord injury

Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate. ²² It causes pain and neurological symptoms. ²³ Individuals who sustain a traumatic SCI often have a loss of multiple body systems. ²⁴ These sequelae greatly affect the ability to undertake daily activities and negatively impact on quality of life. These disorders are generally treated with medications and rehabilitation, but often with limited efficacy. ²³ PRP is a rich source of growth factors and has been used to stimulate the regeneration of peripheral nerves and reduce pain in neurodegenerative disorders. ¹³

A study was undertaken in 60 adult male Wistar rats to investigate the effect of CB-PRP on SCI-induced neuropathic pain. ¹² The rats were randomly divided into six groups: control, sham, SCI, vehicle (SCI + platelet-poor plasma), SCI + CB-PRP 2 day (injection 48 h after SCI) and SCI + CB-PRP 14 day (injection 14 days after SCI). ¹² SCI was induced at the T12–T13 level. ¹² Behavioural tests were conducted weekly after the SCI for 6 weeks. ¹² Allodynia and hyperalgesia were assessed using acetone drops, plantar test and von Frey filament. ¹² Cavity size and the number of fibroblasts were determined by haematoxylin and eosin staining of tissue sections. The levels of the mammalian target of rapamycin (mTOR), the phospho-mTOR, the P2X3 receptor and the P2Y4 receptor were determined using Western blot analysis. ¹² The results showed that CB-PRP reduced SCI-induced allodynia and hyperalgesia by regulating ATP signaling. ¹²

A subsequent study by the same research teach investigated whether CB-PRP could recover motor function in animals with SCI. ¹³ Sixty adult male Wistar rats were randomly divided into six groups: control, sham (laminectomy without induction of SCI), SCI, vehicle (SCI + platelet-poor plasma), CB-PRP 2 day (SCI + CB-PRP injection 2 days after SCI) and PRP 14day (SCI + CB-PRP injection 14 days after SCI). ¹³ SCI was performed at the T12–T13 level. ¹³ The Basso, Beattie and Bresnahan (BBB) locomotor scale was undertaken weekly after injury for 6 weeks. ¹³ Caspase 3 expression was determined using immunohistochemistry. The levels of glycogen synthase kinase-3β (GSK3β), cerebrospinal fluid (CSF) tau and myelin-associated glycoprotein (MAG) were determined using Western blot analysis. ¹³ The results showed that CB-PRP enhanced hind limb locomotor performance by modulation of caspase 3, GSK3β, CSF tau and MAG expression. ¹³

Research on CB-PRP in wound and dermatological disorders

The skin is the largest organ in the human body, the diseases of which are very common. The skin is affected by various diseases with complex aetiologies that cannot be effectively addressed using currently available therapeutic agents. ²⁵ For decades, finding pioneering effective long-term or disease-modifying treatments for dermatological disorders has been a major focus of scientists. The conventional drug delivery systems have demonstrated suboptimal efficacy at high doses and are associated with side-effects, which lead to challenges in adherence to therapy. ²⁶

A previous pilot study treated 12 patients with dystrophic (dermolytic) epidermolysis bullosa (DEB) with CB-PRP gel during 2014–2017. ¹⁴ Eight patients showed good-to-very good results, while the treatment was minimally (–/+ to +) or not effective (–) in two patients and two patients, respectively. ¹⁴ Patients and their parents did not report untoward effects associated with CB-PRP gel treatment. ¹⁴ The promising clinical evidence obtained in this previous pilot study support the development of larger controlled clinical trials to compare the efficacy of CB-PRP gel obtained from cord blood versus traditional A-PRP prepared from adult blood donors and versus current standard approaches of wound care in these patients. ¹⁴

Another study evaluated the safety and efficacy of the use of CB-PRP gel combined with a hydrogel dressing in 10 patients with chronic venous ulcers. ¹⁵ CB-PRP was combined with a carboxymethyl cellulose (CMC)-based hydrogel dressing, which was applied once a week for 4 weeks; and 80% of patients had a significant decrease in wound size after 4 weeks of treatment. ¹⁵ Moreover, the mean wound bed score, numeric rating scale value and the EQ-5D index score were improved, which suggests that the topical application of CB-PRP in combination with a CMC-based hydrogel dressing has the potential to accelerate the healing of chronic lesions without adverse reactions. ¹⁵

In March 2024, the ‘Platelet Rich Plasma Combined With Human Umbilical Cord Mesenchymal Stem Cells for Stage 3 and 4 Stress Injury’ clinical trial was listed on ‘clinicaltrials.gov’ (ClinicalTrials.gov ID NCT06302582). It is currently recruiting and aims to enrol 40 patients. It aims to evaluate of the efficacy and safety of hUC-MSCs combined with CB-PRP and is projected to be completed in November 2024. Stress injury is a globally prevalent health issue and significantly reduces the quality of life of patients and their families. CB-PRP is expected to play a considerable role in safely and effectively treating skin diseases, alleviating patient suffering and reducing their economic burden.

A cytological study was designed to compare the effects of human adult peripheral blood and CB-PRP on the proliferative and migratory abilities of human skin fibroblasts. ¹⁶ CB-PRP (5, 10, 15, 20 and 50% PRP) and adult peripheral blood were added to fibroblasts cultured from a human skin sample. ¹⁶ The migration and proliferation of fibroblasts were assessed in comparison with 10% fetal bovine serum and by the fibroblast responses to a concentration gradient. ¹⁶ As anticipated, the results showed that all components of the CB-PRP significantly stimulated the growth of fibroblasts when compared with the negative control. Importantly, fibroblast growth was enhanced in a dose-dependent manner. All fibroblast cultures retained a normal morphology. ¹⁶ These findings collectively suggest that CB-PRP can be safely used to treat chronic wounds without triggering an immune response. ¹⁶

Research on CB-PRP in gynaecological diseases

The human endometrium is a highly dynamic, regenerative and complex tissue that repeatedly undergoes a cycle of proliferation, differentiation and renewal, approximately every 28 days, in preparation for embryo implantation and successful pregnancy during the female reproductive life.^17,18 While endometrial renewal is usually efficient, pathologies or disorders, such as Asherman’s syndrome (AS) or endometrial atrophy (EA), may result in recurrent pregnancy loss or infertility. AS is defined by the presence of intrauterine adhesions, which contribute to a partial or complete absence of functional endometrium, while EA is characterized by insufficient endometrial growth. Women suffering from AS or EA have a lower probability of a successful pregnancy owing to impaired implantation and early abortion. ¹⁸ However, until now, there has not been a completely effective and reliable therapy. ¹⁸

A previous study evaluated whether CB-PRP can be used to treat AS and EA. ¹⁷ The CB-PRP (n = 3) was processed, characterized and delivered locally to endometrial damage in a murine model (n = 50). ¹⁷ The CB-PRP was either used alone or loaded into a decellularized porcine endometrium-derived extracellular matrix hydrogel. ¹⁷ Endometrial regeneration, fertility outcomes and immunocompatibility were evaluated 2 weeks following treatment administration. ¹⁷ The results demonstrated no apparent harm to the treated animals and there was an improvement in their endometrial health and they achieved pregnancy, which suggests that CB-PRP could have a healing effect on endometrium. ¹⁷

Another study investigated the possible beneficial effects of different sources (CB and adult peripheral) of PRP on patients with AS/EA. ¹⁸ The results showed the highest increase in in vitro proliferation and migration rate was found when endometrial stromal cells were treated with CB-PRP. ¹⁸ In the mouse model, the damaged uterine tissue showed more proregenerative markers after applying CB-PRP compared with adult PRP. ¹⁸ These findings suggest that the regenerative effects of CB-PRP on endometrial pathologies seem to be more pronounced compared with adult PRP. ¹⁸

In addition, the ‘Umbilical Cord Plasma for Treating Endometrial Pathologies (Thin Endometrium/​ Asherman's Syndrome/​ Endometria Atrophy) (hSCU-PRP)’ clinical trial was registered on clinicaltrials.gov in April 2022 (NCT05095597). It plans to enrol 45 patients and complete the study by November 2024. In this study, the investigators have included a ‘proof of concept' group (women with premature ovarian insufficiency) to obtain a deeper understanding of the clinical value of CB-PRP. Positive outcomes are anticipated from this study.

Restoring ovarian function in patients with premature ovarian failure (POF) undergoing chemotherapy is an important problem in the field of reproductive medicine. At present, hUC-MSCs have been used in the treatment of POF, but the effect is still not optimal. ¹⁹ In order to elucidate the effects of CB-PRP on enhancing the beneficial effects of hUC-MSCs in the treatment of POF, this previous study initially examined the effect of changes in the biological activity of CB-PRP on hUC-MSCs in vitro. The study then measured the distribution and function of the hUC-MSCs in POF rats. ¹⁹ The oestrus cycle, serum sex hormones, follicular development, ovarian angiogenesis, ovarian granulosa cell proliferation and apoptosis were assessed. ¹⁹ The finding of this research suggests that the combined application of hUC-MSCs and CB-PRP was a safe and efficient transplantation programme for the treatment of POF. ¹⁹

Research on CB-PRP in ophthalmic diseases

Age-related macular degeneration (AMD) is an increasingly important public health issue that is attributed to ageing populations and increased longevity. ²⁷ It is the second leading cause of irreversible blindness in adults over 50 years old. ²⁸ AMD is a multifactorial disease that results from a combination of genetic and environmental risk factors. The strongest environmental risk factors are age and lifestyle factors, such as smoking, obesity and dietary habits. ²⁹ The disease progresses from an asymptomatic early stage to the late stages of either dry (geographic atrophy) or wet (neovascular) AMD. Dry AMD is usually slowly progressive and is characterized by choriocapillaris and retinal pigment epithelium loss, which eventually leads to the formation of atrophic patches with accompanying photoreceptor degeneration; and there is no treatment available to date. ³⁰ Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration of rod photoreceptors, which is followed by the degeneration of cone photoreceptors. ³¹ RP is one of the leading causes of visual disability and blindness in people under 60 years of age and it affects over 1.5 million people worldwide. ³² There is currently no curative treatment for people with RP. ³²

For AMD and RP, Fondazione Policlinico Universitario Agostino Gemelli IRCCS has listed two clinical trials on clinicaltrials.gov: (i) ‘Cord Blood Platelet-rich Plasma (CB-PRP) in Retinitis Pigmentosa and Dry Age-related Macular Degeneration’ (ClinicalTrials.gov ID: NCT04636853); and (ii) ‘Atrophic Age-related Macular Degeneration (AMD) Treated With Intravitreal Injections of Umbilical Cord Blood Platelet-rich Plasma (CB-PRP): a Pilot Study’ (ClinicalTrials.gov ID: NCT05706896). The trials aim to evaluate the effect of CB-PRP on reducing or stabilizing the atrophic progression in bilateral dry AMD. The first study enrolled 20 patients, aged 18–70 years, who accepted subretinal injection of CB-PRP in one eye, while the other eye served as the control. This trial concluded on 2 December 2021, but no results have been published to date. The second study is currently recruiting and aims to enrol 36 patients, aged ≥65 years, who will receive intravitreal injections of CB-PRP. Although no outcomes have been published from either trial to date, there is optimism that CB-PRP has a role to play in treating ophthalmic diseases.

Discussion

Research reports on PRP can be traced back to the 1950s.^33,34 However, its application in the treatment of diseases did not begin to emerge in the form of autologous use until the 1980s.^35,36 More recently, the research into and application of PRP have been expanding rapidly. In contrast, research on CB-PRP is more recent, only emerging in the last decade. ⁸ Thus, reports on the use of CB-PRP in the treatment of diseases are rare.

Compared with A-PRP, CB-PRP possesses distinct characteristics and advantages. A-PRP is derived from the patient’s own blood and is affected by their own health status, so it might not be suitable for use or it might have limited applicability and efficacy. Conversely, CB-PRP is derived from umbilical cord blood collected at birth and it is meticulously screened and tested to ensure safety and quality, so it can be selectively applied according to the individual patient's conditions, treatment requirements and prognosis.

It has been generally accepted that the younger the source of PRP, the higher its regenerative potential is.^18,37 This is thought to be linked to the higher concentration of growth factors, anti-inflammatory molecules and proangiogenic factors found compared with plasma from an older donor.^6,38,39 The effect of the age of the donor has been functionally validated with the use of in vitro and in vivo assays.^6,18,37–39 There are also several ongoing clinical trials using CB-PRP. ¹⁸ In vitro results also indicate a significant increase in cell proliferation and migration following CB-PRP treatment compared with adult PRP. ³⁹ In addition, the decision to use A-PRP should be made on an individual basis, a choice that is influenced not only by the condition of the patient, but also by the qualifications and medical facilities available at the hospital. However, CB-PRP, similar to regular medications, can be used in a wide range of patients as and when required and is subject to relatively fewer medical conditions.

However, because CB-PRP is a heterologous product, the risks might be greater compared with using autologous A-PRP, which warrants a more cautious approach in its clinical research and application. At present, research in CB-PRP use has only been reported in the aforementioned fields. However, given the increasing number of diseases in which A-PRP is being applied, it is only a matter of time before CB-PRP is widely studied and used.

Conclusion

In conclusion, CB-PRP has distinct characteristics and advantages over A-PRP. Despite the relatively short history of research into and application of CB-PRP, it has shown encouraging preliminary results in several diseases. CB-PRP is expected to play a pivotal role in bone regeneration, spinal cord injury repair, wound healing and the treatment of certain gynaecological diseases. It is believed that CB-PRP will be comprehensively studied in more medical fields in the near future. It is expected to replace A-PRP in some patients where A-PRP is not applicable.