INTRODUCTION:

Diabetes is said to be the rapidly growing global burden. It was estimated that its prevalence will rise to 12%, which is around 783 million people by the year 2045¹. These people are highly vulnerable to macro and microvascular complications in a silent diabetic state². The most prevalent complication due to diabetes is Diabetic Ulcer (DU), which is associated with increased morbidity and mortality rate^3-6. The management of DU is also highly complex with high incidence worldwide^7-13.

Hence, DFU has become a serious global health issue with presently limited available treatment options like debridement of wound, wound dressing and infection control^14,15. With these available treatment options, the evidence shows that the average recovery time in the absence of surgery is about 12 weeks¹⁶. Thus, impactful, immediate and inexpensive treatment options for DFU is much needed at present.

As a result, Platelet Rich Plasma (PRP) gained enormous interest which has the growth factor containing platelets needed for tissue regeneration and repair^17-20 PRP is commonly prepared from autologous blood. Hence it is widely appreciated as safe in terms of non-contamination of diseases and unaffected^21,22.

Many studies have found that PRP has potential clinical application in regeneration of bone and skin tissues^23-27. When the PRP is activated by adding thrombin, it causes release of various biomolecules like cytokines and growth factors^28,29.

The scope of the present review is to explore comprehensively all the possible mechanisms behind PRP therapy and its vital role in inducing wound healing in DFU.

MATERIALS AND METHODS:

Eligibility Criteria:

The purpose of this review is to analyse the curative potential of PRP in DU, targeting its mechanism of action. The inclusion criteria were those studies on DU and Chronic diabetic wound, PRP treatment of any form, mechanism on wound healing. The study design includes cohort studies, Randomized Control Trials (RCT), observational studies and case-control studies that are published in English.The exclusion criteria include studies that are not related to diabetic wound, that does not have sufficient data and report.

Information Sources and Search Strategy:

A complete review of literature was done from the databases like SCOPUS, PubMed, Cochrane Library, Web of Science and Google Scholar.

Study Selection Process:

The studies were reviewed and selected based on PRISMA guidelines.

Risk of Bias and Quality Assessment:

The studies which were included was assessed for risk of bias with the help of Newcastle-Ottawa Scale for observational studies and Cochrane Risk of Bias Tool for RCT studies. Then the quality of each study was rated and studies with high bias risk was rejected.

Synthesis of Data:

The findings from these studies were summarized as a narrative form with the primary focus on PRP mechanism, its therapeutical potential in diabetic wound healing. Since there exists a heterogeneity in study outcome and designs, a meta-analysis was not workable.

RESULTS AND DISCUSSION:

DIABETIC ULCER:

Diabetic Foot Ulcer (DFU) which is commonly known as Diabetic Ulcer (DU) or diabetic wound is characterised by altered normal healing environment due to diabetes. The underlying aetiopathogenesis behind DU is complex and consist of various factors like neuropathy, impaired blood flow, Oxidative Stress (OS) and poor cellular proliferation due to impaired growth factor production.

In Diabetes Mellitus (DM), the major factors contributing to foot ulcers are Peripheral Vascular Disease (PVD) and Diabetic Neuropathy (DN) ³⁰. Impaired blood flow occurs which is complicated by endothelial dysfunction and inadequate nitric oxide production in diabetes³¹.

There will be delay and failure of natural mechanism of cell migration and activation leading to failure of wound healing^32-34. Because of this, the DU become refractory and chronic in many patients. This is due to ongoing chronic inflammation due to release of pro-inflammatory cytokines like TNF (Tumor Necrosis Factor)-α and IL (Interleukin)-1³⁵.

As a result of hyperglycemia in diabetes, there will be enhanced formation of Advanced Glycation End products (AGE). This leads to increased release of inflammatory cytokines which prevents the normal mechanism of wound healing in DU^36,37. The outcome of this chronic inflammation is elevated production of Reactive Oxygen Species (ROS) causing an OS. This further impairs and exacerbates the inflammation leading to poor wound healing³⁸.

Hyperglycemia paves way for easy infection and bacterial growth in ulcer, which again delay the wound healing process. Also, the underlying chronic inflammation in diabetes also complicates this process³⁹.

These factors are further complicated by inadequate production of essential factors for wound healing like PDGF, EGF and VEGF^40,41.

Limitations and challenges in current diabetic wound care:

The management of DU remains challenging due to availability of limited and conventional treatment options like wound debridement, ulcer dressing and fewer topical therapies. No single treatment was found to be completely effective and superior in managing DU⁴².

It was estimated that around 40% of DU patients had repeated ulcer in the same year⁴³. The average healing period in case of DU was found to be around 154 days which shows its chronicity⁴⁴.

The conventional treatment often fails to address the root cause of DU like poor blood flow, DN and OS⁴⁵. Hence, the need for more efficient therapy in healing DU is much needed at present.

PRP PREPARATION:

PRP is known as a bioactive material isolated from autologous blood. This is been used in various branches of medicine like tissue engineering, wound healing and regenerative medicine. The efficacy of PRP depends upon its way of preparation. Routinely, the preparation of PRP is by 2 techniques namely, the open and the closed method^46,47. The most preferred method for preparation of PRP is open method, as it yields good amount of platelet. These methods need to be optimized to enhance its safety and efficacy.

MECHANSIM OF PRP:

Growth Factor-Mediated Angiogenesis:

Growth factors like PDGF, TGF-β and VEGF are known as pro-angiogenic stimulators.

PRP consist of growth factors like TGF– β, PDGF, EGF, Platelet-Derived Angiogenesis Factor (PDAF), Platelet Factor 4 (PF-4), Platelet-Derived Epidermal Growth Factor (PDEGF), Vascular Growth Factor (VGF), VEGF ^48-53. These factors are found to have role in cell attachment, migration, proliferation and differentiation. Also, they play vital role in tissue regeneration and ulcer healing, by promoting deposition of Extracellular Matrix (ECM)^54-56.

During the treatment process using PRP, the platelets are activated and release various growth factors are that bind to receptors present on the surface of endothelial cells. This causes activation of the endothelial cells. These endothelial cells migrate to the site of wound, where they proliferate⁵⁷. Finally, these proliferated endothelial cells are involved in a process known as tubulogenesis. This is a process of formation of new blood vessel, by appearance of lumen. Hence, finally they become as functional blood vessels⁵⁸. This leads to neovascularization at the site of diabetic ulcer. Because of neovascularization, there will be increased blood flow causing increased oxygen delivery to the wound site⁵⁹.

· PDGF:

PDGF is present in alpha granules of platelets and is available in 3 isoforms, which are PDGF-AB, PDGF-AA and PDGF-BB which consists of A and B chains⁶⁰. It is also said to be present in various cells like endothelial cells, fibroblasts, macrophages and monocytes. The major functions of these isoforms in diabetic wound healing are angiogenesis, matrix deposition and wound contraction⁶¹. In a wound, the first growth factor to appear is the PDGF⁶². Overall, it is involved in regeneration and repair in the process of healing damaged tissues^63,64.

PDGF binds to PDGF receptor (alpha receptor) leading to a series of intracellular reactions. At first, they mediate the migration of other undifferentiated cells into the area of injury thereby making the beginning of healing process. The outcome consists of revascularization and angiogenesis in which new blood vessels are formed. It also leads to proliferation of regenerative cells and stimulation of macrophages to activate. This results in wound cleaning⁶⁵. Hence it was found that application of PRP in form like autologous PRP gel has resulted in accelerated and early wound closure in case of diabetic ulcer due to presence of these growth factors⁶⁶.

· VEGF:

VEGF is discharged by cells such as platelets and macrophages. It is important for the process of angiogenesis, as it provokes the new blood vessel formation. This leads to enhanced oxygen and nutrient supply to the wound. Additionally, it triggers the proliferation and migration of endothelial cells and increases the vascular permeability⁶⁷.

· TGF-β:

It belongs to superfamily of TGF-β, that has bone morphogenetic proteins. It plays a vital role synthesis of collagen and helps preventing its breakdown. It also enhances the process of angiogenesis and chemotaxis of immune cells^68,69.

· EGF:

EGF is responsible for differentiation and proliferation of epithelial cells, reinforce angiogenesis and intensifies the process of wound healing. It also amplifies the cytokine release from epithelial and mesenchymal cells^70,71.

· IGF (Insulin like Growth Factor) -1:

It is known as a polypeptide hormone, which is present in plasma. It is said to be transported by platelets. It activates the process of mitogenesis and differentiation of mesenchymal cells⁷².

· FGF (Fibroblast Growth Factor):

This is said to be growth factor with most efficient mitogenic effect. It aids in proliferation of cells like chondrocytes, mesenchymal cells and osteoblasts. It is crucial for the process of angiogenesis along with VEGF. The overall effect promotes the growth of these cells⁷³.

· HGF (Hepatocyte Growth Factor):

The so-called HGF is present in cells like mesenchymal and platelet. It provokes the process of cell motility and mitogenesis in the mechanism of wound healing. Additionally, it controls the cell growth and motility of endothelial and epithelial cells, accelerates angiogenesis and aids in repair of epithelium.

Inflammation modulation:

PRP consists of various cytokines like IL-6, IL-1β, IL-8, TNF-α, Monocyte Chemotactic Protein-1 (MCP-1), IL-10, Macrophage Inflammatory Protein-1 (MIP-1) that play very important role in wound healing.

The most important among them that are responsible for mediating immediate responses are TNF-α, IL-1 and IL-6^74,75. The major motive in using PRP in wound healing is halting the existing catabolic and inflammatory microenvironment. It controls the inflammatory damage and repair of tissues. The anti-inflammatory cytokines are involved in controlling the proinflammatory action of cytokines that are released by activated macrophages⁷⁶. The commonly involved anti-inflammatory cytokines are IL-4, IL-11, IL-10, IL-13 and IL -1 receptor antagonist. Based on the type of wound, some cytokines exert anti or pro inflammatory effects. They are IL-6, TGF-β1, Leukaemia Inhibitory Factor (LIF) and INF (Interferon)-alpha. Additionally, these cytokines are involved in wound healing by stimulating pathways that are involved in activating fibroblast⁷⁷. Certain pro-inflammatory cytokines like IL-6, Il-1, IL-12, TGF-β1 and IL-33 are involved in mediating the differentiation of fibroblast into myofibroblasts. These fibroblasts cause release of IL-33, IL-1, CXC, TGF and CC chemokines that attract and activate macrophages thereby leading to pro-inflammatory reactions⁷⁸. These inflammatory cells cause tissue regeneration by release of various growth factors, chemokines, metabolites and wound debridement⁷⁹. Hence PRP performs a dual role as it controls the inflammatory damage while simultaneously promoting tissue repair.

· TNF and IL-1β:

It causes activation of macrophages, proliferation of fibroblast, migration of cell like monocyte and mediating the process of angiogenesis.

It was found that IL-1β increases the expression of aggrecan mRNA and type-II collagen and reducing their inhibition⁸⁰. HGF plays a crucial role in acting as an anti-inflammatory cytokine by halting the NF- κB signalling pathway, thereby decreasing inflammation in the site of ulcer⁸¹.

· IL-10:

It plays a very important role in modulation of inflammation by acting as most effective anti-inflammatory cytokine. It causes inhibition of production of pro-inflammatory cytokines like TNF-α, IL-1 and IL-6. It also enhances the release of various anti-inflammatory agents. Hence regulating the function and production of pro-inflammatory cytokines by acting as a negative feedback system.

Overall, the cytokines that are present in the PRP are important in arbitrating immunological responses driving the settlement of inflammatory phase. This entire process is known as “regenerative inflammation”⁸². Hence during the process of wound healing, this inflammatory phase is very important as it stimulate the mechanism of cellular plasticity⁸³.

Role of cells in PRP:

Depending on the method of preparation, it contains any leukocytes. Neutrophils are said to be involved in initial phase of phagocytosis removing necrotic tissue, debris and microbes. The monocytes follow them and produce matrix metalloproteinases like MMP-9, MMP-2 and MMP-13. This helps in degrading the ECM and increasing cellular migration⁸⁴. Finally, monocytes get converted to macrophages which maintains the process of phagocytosis and thereby releasing numerous growth factors like VEGF, TGF- β1, PDGF, EGF and IGF-1. Thereby promoting angiogenesis and tissue repair. Leukocyte rich-PRP can delay the process of wound healing as there can be excessive ROS production by neutrophils⁸⁵. This is normally released to remove debris and microbes in ulcer site⁸⁶. Studies have shown that WBC in PRP can cause both greater inflammation and tissue protection⁸⁷.

Cellular Differentiation and Proliferation:

PRP consists of proteins like fibrin. This protein acts as a scaffold in the process of tissue regeneration. It is also involved in blood clotting, wound closure and wound contraction^88,89. PRP was found to enhance collagen synthesis and fibroblast proliferation⁹⁰. It also causes migration and differentiation of fibroblast and keratinocytes⁹¹. This leads to enhanced tissue healing^92-94.

Antibacterial properties:

Also, PRP when activated releases a numerous antibacterial protein. It was observed that these antibacterial proteins are capable of inhibiting Staphylococcus epidermidis, staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae and Escherichia coli (E. coli). In addition, it exerts a synergistic effect with antibacterial agents, without causing drug resistance^95-97. Hence, it can be used along with regular antibiotics.

THERAPEUTIC POTENTIAL OF PRP:

1. Wound Healing Enhancement:

Previous studies have found that PRP has enhanced the wound healing and decreased the amputation risk in patients with DU^98,99. PRP has become an emerging adjunctive therapy in enabling diabetic wound healing. Marwa et al. in their study has found that using autologous PRP as gel for DU weekly twice has achieved a complete healing in 86% of the patients¹⁰⁰. The total time of complete wound healing in DU was found to be reduced by PRP therapy¹⁰¹.

2. Wound closure:

Previous studies have shown that PRP therapy has resulted in wound closure in DU. A study by McAleer et al. has found that treatment using PRP has significantly increased the rate of wound closure and has caused decreased wound size in DU¹⁰². It was demonstrated to improve the collagen production and enhance cellular proliferation leading to increased wound closure in DU. Similarly, it was proven that by enhancing the wound closure, it has decreased the amputation risk in DU¹⁰³.

3. Angiogenesis and Improved Tissue Perfusion:

Studies have shown that autologous PRP therapy was efficient in increasing the tissue perfusion in DU. This promotes improved wound healing. It was found that PRP treatment in diabetic mice has improved angiogenesis and enhanced tissue perfusion¹⁰⁴. Joeng et al. in their study have found that treatment with PRP has drastically increased tissue perfusion leading to improved wound healing in DU¹⁰⁵.

4. Modulation of Inflammatory Response:

PRP therapy plays a major role in modulating inflammatory response which improved the healing rate in DU^106-108.

5. Antibacterial and Infection Control:

DU are usually superseded by infections further complicating the management. It was found that PRP consists of antimicrobial proteins like TGF-β, PDGF and Thrombospondin -1 that has antibacterial activity against numerous pathogens¹⁰⁹. It was observed that PRP halts the growth of various bacteria like E. Coli, Staphylococcus aureus and Pseudomonas aeruginosa that are frequently found in DU¹¹⁰. It significantly decreased the bacterial load leading to enhanced wound healing.

6. Pain Reduction and Comfort Enhancement:

PRP treatment in DU has shown to decrease pain and thereby increase the comfort in patients. It was believed to be due to modulation of inflammation by PRP in DU management¹¹¹.

COMPARISON OF PRP TO OTHER TREATMENT:

At present PRP is said to be an emerging option in treating DU and has shown superior when compared to other modalities of DU management. Table 1 represents the comparison PRP with other treatment used in DU.

Overall, PRP holds great promise for the treatment of DU, particularly for patients with chronic, non-healing wounds, though more research is needed to optimize its use and broaden its applicability.

AUTHOR CONTRIBUTION:

The author conceptualized the review article, conducted a comprehensive literature search, analyzed the relevant studies, and synthesized the findings. The writing and revision of the manuscript were carried out solely by the author. The author is also responsible for the final approval of the manuscript and its submission for publication.

ACKNOWLEDGEMENT:

The author would like to express gratitude to the researchers and clinicians whose work has contributed to the advancement of diabetic wound care and PRP therapies, which formed the foundation of this review. Special thanks are extended to the institutions and funding bodies that support ongoing research in this field. Additionally, the author appreciates the invaluable feedback and support from peers and colleagues throughout the writing process.

CONFLICTS OF INTEREST:

The author states that there are no conflicts of interest.

FUNDING:

This article was prepared without any financial backing, grants, or external assistance.

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Received on 29.12.2024 Revised on 15.02.2025

Accepted on 24.03.2025 Published on 10.07.2025

Available online from July 17, 2025

Asian J. Pharm. Res. 2025; 15(3):337-346.

DOI: 10.52711/2231-5691.2025.00053

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Comparison	PRP	Other treament	Study outcome	Reference
1. PRP vs. Conventional Dressings	Provides essential growth factors to enhance tissue regeneration and wound healing.	Conventional dressings (foam, gauze, film) act as physical barriers but do not treat the root cause of DU.	PRP improves wound healing by addressing the root cause, unlike conventional dressings.	112,113
2. PRP vs. Antimicrobial Dressings	Exhibits antimicrobial properties, promoting a healthy environment for wound healing.	Antimicrobial dressings (antibiotics, iodine, silver) help prevent bacterial growth but can lead to antibiotic resistance.	PRP provides a healthier environment by reducing infection risk without causing antibiotic resistance.	114-121
3. PRP vs. Autologous Skin Grafts	Enhances wound healing without the risk of graft rejection and fewer side effects.	Autologous skin grafts can lead to graft rejection and donor site morbidity.	PRP offers a non-surgical alternative with fewer complications than skin grafting.	122-124
4. PRP vs. Growth Factor Therapy	Rich in growth factors and platelets, prepared from autologous blood, inexpensive, and promotes wound healing.	Growth factor therapy uses recombinant growth factors (VEGF, PDGF, FGF) but can be expensive.	PRP is more cost-effective and contains a natural source of growth factors, enhancing healing.	125-127
5. PRP vs. Negative Pressure Wound Therapy (NPWT)	Cost-effective, enhances healing with fewer side effects, and no wound destruction.	NPWT is expensive, may cause tissue destruction, and requires longer treatment durations.	PRP offers better healing with fewer side effects and a healthier wound environment compared to NPWT.	128-130
6. PRP vs. Hyperbaric Oxygen Therapy (HBOT)	Cost-effective, promotes better healing and ulcer closure.	HBOT increases oxygen delivery, promotes collagen synthesis, but is more expensive with fewer studies supporting its efficacy.	PRP is more cost-effective and shows comparable or better healing outcomes than HBOT.	131,132