Application of Platelet-Rich Plasma-Based Scaffolds in Soft and Hard Tissue Regeneration

Abstract

Platelet-rich plasma (PRP) is a blood product with higher platelet concentrations than whole blood, offering controlled delivery of growth factors (GFs) for regenerative medicine. PRP plays pivotal roles in tissue restoration mechanisms, including angiogenesis, fibroblast proliferation, and extracellular matrix development, making it applicable across various regenerative medicine treatments. Despite promising results in different tissue injuries, challenges such as short half-life and rapid deactivation by proteases persist. To address these challenges, biomaterial-based delivery scaffolds, such as sponges or hydrogels, have been investigated. Current studies exhibit that PRP-loaded scaffolds fix these issues due to the sustained release of GFs. In this regard, given the widespread application of PRP in clinical studies, the use of PRP-loaded scaffolds has drawn significant consideration in tissue engineering (TE). Therefore, this review briefly introduces PRP as a rich origin of GFs, its classification, and preparation methods and discusses PRP applications in regenerative medicine. This study also emphasizes and reviews the latest research on the using scaffolds for PRP delivery in diverse fields of TE, including skin, bone, and cartilage repair.

Impact Statement

Platelet-rich plasma (PRP) is a blood product with high platelet concentrations, offering managed delivery of growth factors (GFs) for regenerative medicine. This review briefly introduces PRP as a rich source of GFs and discusses PRP-loaded scaffold applications in soft and hard tissue including skin, bone, and cartilage restoration. In the current study, the applications of PRP-loaded scaffold in soft and hard tissue regeneration (skin, bone, and cartilage) were discussed in detail.

Introduction

Tissue engineering (TE) is an impressive part of biomedical research that has emerged over the past decades, focusing on the cartilage restoration, repair, or replacement of injured or dysfunctional organs and tissues.¹ Fundamentally, scaffolds, biological products including cells, and growth factors (GFs) are the prominent components of TE-based strategies.² Scaffolds are three-dimensional biomaterial-based constructs created from biodegradable and biocompatible polymers. These structures resemble the extracellular matrix (ECM), offer mechanical support for cells to attach, grow, and migrate, and also can be utilized to release GFs.³ Over the recent decades, there has been extensive research on various biomedical applications of scaffolds.^4–8 Generally, in clinical studies, the designed scaffold is combined with cells or GFs and cultured in suitable conditions. Afterward, the prepared construct is implanted in vivo to conduct its desired function.⁹ Recently, PRP, a hemoderivative type of biological product that is a cocktail of various GFs, cytokine, and biomolecule, has become an attractive therapeutic tool in restoring the injured tissue caused by damage or chronic illnesses.¹⁰ The synergy of these various bio components in plasma and platelets is the PRP-based therapy central cores.¹¹ On the contrary, PRP has drawn remarkable attention in tissue regeneration, which is related to its safety, straightforward preparation, and low-cost processing.¹² The standard procedure for administering PRP is including patient’s whole blood extraction and centrifugation, followed by its component concentration. Finally, the activated PRP will be delivered to damaged body parts that need to be repaired.¹³ Administered PRP may trigger the release of GFs that can accelerate the healing and restoration processes by starting the hemostatic cascade and stimulating revascularization. In addition, connective tissue formation may occur around the injured site.^14,15 As mentioned above, PRP is an autologous biological component with no adverse side effects, making it appropriate for a variety of biomedical applications.¹⁶ Although PRP injection into the damaged tissue is the main route of its administration, its effectiveness may be limited by drawbacks such as short lifespan and immediate inactivation in the site of action. To solve these challenges, later studies have focused on developing bioengineering approaches such as applying scaffolds for PRP delivery in a controlled manner.¹⁷ By utilizing this delivery system, the short circulation time and half-life of PRP components are increased, which leads to their stability and durability improvement.¹⁸ In this study, following the introduction of PRP and its applications in tissue regeneration, we had a comprehensive review of scaffold-based PRP delivery in soft and hard tissue regeneration. We have also included findings from previous research on PRP-loaded scaffold incorporation in skin, bone, and cartilage tissue restoration.

An Overview of PRP

The “PRP” term was first raised in the 1970s by hematologists to describe plasma that contains a greater number of platelets compared with peripheral blood. Initially, it was utilized to treat patients with low platelet counts, specifically in the context of blood transfusions.¹⁹ Platelets are cytoplasmic fragments derived from megakaryocytes found in the bone marrow, with a diameter of ∼2 μm,²⁰ which contain over 30 bioactive proteins, including numerous coagulation factors, adhesion molecules, chemokines, cytokines, integrins, and GFs, such as VEGF, ECGF, FGF, IGF-1, EGF, PDAF, PDGF, HGF, and TGF-β.^21,22 Every single GF, which was mentioned earlier, has a vital role to play in hemostasis or tissue healing (listed in Table 1).³² Furthermore, PRP contains macrophage and monocyte mediators, as well as inflammatory mediators called interleukins (IL).³³ In a general manner, three granules (alpha, delta, and lambda) are inside the platelets. Alpha granules are the most plentiful type of platelet granules³⁴ and are composed of both membrane-bound and soluble proteins that are freed into the extracellular space. Earlier research indicated that over 300 soluble proteins involved in various processes, such as inflammation, blood clotting, immune response, cell adhesion, and growth, and potentially other lesser-known functions are secreted by α-granules.³⁵ Delta forms (dense bodies) are the second common type of platelet granules. Delta granules are mainly made up of clotting-promoting molecules, such as calcium, magnesium, and adenosine, as well as bioactive amines (serotonin and histamine). Lambda granules are composed of enzymes that have a fundamental role in degrading proteins, lipids, and carbohydrates. In addition, they are responsible for cleaning up damaged tissue and eliminating infectious agents.^36–38 Via activation (e.g., with Calcium chloride (CaCl₂)), one of the main steps in PRP preparation, the granules present in platelets fuse to its cell membrane (named degranulation) where it releases GFs in high concentrations.³⁹ A broad range of target cells, including mesenchymal stem cells (MSCs), endothelial cells, fibroblasts, osteoblasts, and epidermal cells, are exposed due to the secretion of active proteins.⁴⁰ Over the recent years, there has been a significant interest in PRP therapy in the medical field due to its favorable benefit–risk ratio and good safety profile. This interest has arisen as a result of the therapy’s promising outcomes and lack of severe adverse effects.

Table 1.

Growth Factors in PRP and Their Biological Functions

VEGF	Enhances angiogenesis, endothelial cell migration, and proliferation Repairs bone defects²³ Induces wound healing via collagen deposition and epithelialization²⁴
ECGF	Promotes angiogenesis Promotes proliferative effect of endothelial cells Is a chemotactic factor²⁵
IGF-1	Stimulates normal growth of bones and tissues²⁶
PDGF	Has a fundamental role in the wound healing Increases cell proliferation, migration, and angiogenesis²⁷
TGF-β	Plays vital roles in tissue regeneration and differentiation in vertebrates Controls the immunological response and tissue healing Controls metabolism and cell activity in cartilage and bone tissues throughout the ontogenetic human development²⁸
EGF	Promotes the production of elastin and collagen, extracellular remodeling²⁹ Induces cell proliferation and help in wound healing³⁰
HGF	Improves blood vessel regeneration and aids in the development and revascularization of tissue-engineered bone³¹

ECGF, endothelial cell growth factor; EGF, epidermal growth factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor; PDGF, platelet-derived growth factor; PRP, platelet-rich plasma; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.

Platelet-Rich Plasma Classification

Platelet-rich plasma (PRP) types are including: Pure Platelet-Rich Plasma (P-PRP), or leukocyte-poor platelet-rich plasma, is the most commonly applied in dermatology; Leukocyte- and Platelet-Rich Plasma (LPRP), primarily utilized for orthopedic issues and wound healing; Pure Platelet-Rich Fibrin (P-PRF), mainly applied in oral and maxillofacial surgeries; and leukocyte and Platelet-Rich Fibrin (L-PRF), which are effective for wound healing, periodontics, and sports medicine.⁴¹ To categorize platelet concentrates (PCs) clearly, three main parameters are required. An initial set of parameters involves the centrifuge steps and preparation kits. In addition, there is the content of the concentrate, which is the second type of parameter and the third set of parameter is related to the fibrin network that supports the platelet and leukocyte concentrate during use. These data frequently appear to be empirically defined, and cross-examination of this technical information has not been fruitful. In addition, it is not possible to determine if experiments have been carried out using P-PRP or L-PRP. Nonetheless, P-PRPs appear to be the PCs that have undergone the most extensive testing in both in vitro and in vivo studies, even though conducting a thorough review of all the available literature is not practical.⁴²

PRP Preparation Methods

The preparation method significantly impacts PRP composition.^43,44 Healthful individuals have 150,000–350,000 platelets/µL of whole blood, whereas PCs contain 1,000,000 plates/µL of platelet preparation. Various kits are available for PRP preparation, aiming to raise platelet concentrations three- to five-fold above baseline.⁴⁵ PRP preparation can be accomplished in a numerous techniques, but differential centrifugation is a common approach.⁴⁶ As a general rule, either plasma-based (PRP) or buffy-coated (BC) approaches can be used for its preparation (Fig. 1).⁴⁷ The two processes begin with white blood cells (WBCs) but differentiate in how the different components of the blood cells are isolated and concentrated during centrifugation.⁴⁸ It is possible to isolate plasma and platelet components from WBCs using plasma-based methods. The technique involves separating whole blood into platelets and red blood cells (RBCs) by a “soft spin,” followed by a “hard spin” to obtain plasma and platelet concentrates. After the removal of most plasma, platelets are maintained in a smaller volume of the remaining plasma.⁴⁹ Using the BC approach, whole blood undergoes a “hard spin” to separate plasma, RBCs, and buffy coats. It takes 1–2 h for the separated BC to rest, subsequently a “soft spin” is performed on the BC to produce PC. It takes less time to separate components using plasma than BC since a compulsory downtime of 1–2 h is required for the latter. It is important to note, however, that the BC method of component separation has some upsides over other methods, such as lower contamination with WBCs, and higher yield of plasma and platelets. The PRP approach of platelet preparation involves subjecting PRP to a “hard spin” that leads to the creation of aggregates that cause platelets to activate. On the contrary, a “hard spin” of the BC method causes platelets to be cushioned between RBCs instead. As a result, PRP generates less activated platelets than PRP.^50,51 Basically, several factors can affect the yield of PRP, including how is blood drawn, time and temperature of centrifugation, and utilization of anticoagulants.⁴⁶

Fig. 1.

The steps of two common PRP preparation method. PRP, platelet-rich plasma.

PRP Applications in Regenerative Medicine

In the 1990s, regenerative medicine emerged as a new area of medicine dedicated to repairing damaged cells, tissues, and organs to restore their functionality.^52–54 Although traditional medicine tends to focus primarily on replacing damaged tissues, this field aims to stimulate self-renewal in the injured site.⁵⁵ As mentioned before, emerging regenerative therapy approaches aim to harness and utilize the body’s own stem cells and autologous GFs. These GFs, which are polypeptide molecules, interact with receptors on target cells to convey signals related to cell movement, growth, specialization, longevity, and secretory functions.⁵⁵ Although TE uses natural GFs, there are certain clinical limitations, and GF-enriched bioformulations are difficult to create with precise, cost-effective methods; the use of these materials in biomedical applications is therefore hindered by this limitation.⁵⁶ It has been recognized that PRP-based GF delivery is an effective strategy to restart the tissue-repair cascade to restore soft and hard tissues damaged by trauma.⁵⁷ Using PRP has some advantages, for instance, obtaining the PRP from a patient’s blood is simple. A technique using autologous PRP was first presented by Ferrari et al. in 1987 for cardiac surgery.⁵⁸ In addition, PRP is considered safe and natural due to the fact that it uses your own cells without any further modifications. This also makes sure that the preparations do not trigger an immune response.⁵⁹ Second, by controlling the processing technique and activation protocol, it is feasible to regulate the dose of GFs released on activation. The use of PRP in oral and maxillofacial surgery has so far been shown to enhance the healing of both hard and soft tissues, and it is gaining popularity and attention among orthopedic and sports medicine practitioners for treating many different kinds of problems, such as bone, cartilage, ligaments, and tendons.^60,61 Many clinical trials have evaluated PRP’s effectiveness in treating musculoskeletal injuries, including tendinopathies, osteoarthritis, and fractures. The findings suggest that PRP effectively alleviates pain and enhances functionality for individuals experiencing these conditions.⁶² Also, PRP is used in the dermatology sector for procedures, such as facial rejuvenation, hair loss, scar revision, and wound healing.⁶³ As a result of its ability to induce type I collagen synthesis, human dermal fibroblast proliferation, and improve the texture of the skin, PRP is becoming increasingly popular for facial rejuvenation. Dermatologists use PRP to improve the treatment of chronic wounds that pose a serious health concern. Several millions of people around the world suffer from chronic wounds, which can result in infections and amputations if left untreated. Consequently, PRP has been utilized to enhance the healing of chronic wounds, such as diabetic foot ulcers and venous leg ulcers.^10,64 It is crucial to highlight that there are still numerous challenges to tackle regarding the application of PRP in regenerative medicine, particularly concerning the efficient delivery of platelet-derived GFs to specific injury sites, which will be discussed further.

Delivery Systems for PRP-Derived GFs

In most cases, PRP therapy is administered using autologous blood drawn and centrifuged to separate the platelet concentrate from the blood. Once PRP has been activated (typically by CaCl₂ and thrombin), it is injected, applied topically, or combined with surgical procedures at the defect/injury site.⁶⁵ However, there is concern that PRP’s clinical efficacy may be negatively affected by its inefficient and inconsistent delivery of GFs. Due to the quick release of GFs from PRP, their activity may severely diminish within a short period of time.⁶⁶ A GF delivery system used to regenerate or engineer tissues must take several considerations into account. Furthermore, it is crucial to choose a method of factor delivery that will target the desired cell population and minimize the propagation of signals to nontarget tissues and cells. Second, biological activity within the system must be maintained for a relatively long period of time. Third, the release profile of the GF needs to be careful in terms of time and location depending on the tissue injury or disease they are intended to treat.⁶⁷ Therefore, PRP can enhance healing and regeneration and increase bioavailability by combining it with a controlled-release carrier.⁶⁸ To meet the requirement for continuous GF release, scientists have utilized scaffolds as delivery mechanisms for PRP, which will be elaborated on below.

Scaffold-based delivery system

Regeneration of tissues is most commonly accomplished with the direct delivery of GFs at the site of action through a carrier vehicle (scaffold). In addition to maintaining the integrity of a damaged site, scaffolds can prevent PRP from migrating and allow sustained GF release.⁶⁹ The scaffolding environment may also enhance GFs’ bioactivity by facilitating their interaction, leading to different effects than those produced by free-form GFs.⁷⁰ Furthermore, bioactivation can be achieved by incorporating PRP and its derivatives into designed scaffolds. Consequently, it has been possible to design scaffolds with a proper multiscale hierarchical structure over the past decade, as well as delivery systems with the ability to deliver active proteins according to almost any complex pattern in the past decade.⁷¹ An optimal scaffold for TE should function as a framework for three-dimensional tissue development by facilitating tissue infiltration, blood vessel formation, and the transport of nutrients via its interconnected porous structure. In addition, it would promote the differentiation, growth, and preservation of phenotype in the surrounding tissues by engaging with host tissues without creating scar tissue.⁶⁸ This has resulted in scaffold-based delivery systems that come in a variety of configurations, such as hydrogels and sponges, and that use different types of synthetic and natural biomaterials.⁶⁸ The use of nanoparticle delivery systems has also been reported in studies to deliver GFs spatiotemporally.⁷² PRP is delivered locally to the regeneration sites with tissue-engineered scaffolds, covered sutures, or can dissolve in fibrin-like encapsulations in biomaterial-based systems.⁷³ Numerous biomaterials have been tested for the controlled delivery of GFs, and a huge number of experiments are being conducted to find the best method.⁷⁴ As a result, PRP delivered by scaffolds made of biomaterials has quickly gained popularity.⁷⁵ To improve the control of GF release profiles from scaffolds, several techniques have been developed. Many of these strategies focus on embedding GFs within biodegradable polymer networks, allowing for their gradual release into the wound as the scaffold decays. In the future, this process could be enhanced to maintain a therapeutic dose for a longer period compared with the existing fast-releasing scaffolds. PRP-derived GFs can be released in a kinetically controlled manner using hydrogels, sponges, and nanofibers. They are ideal for sustained release and improved bioavailability of GFs at the site of injury because of tailorable scaffold degradation, which impacts the release of included factors.^76,77 As a result, the scaffold material can significantly impact factors such as degradation rate, which, in turn, can lead to variations in PRP component release profiles. In conclusion, it is important to note that the most frequently used biomaterials in clinical applications alongside PRP are natural options such as alginate, collagen, chitosan, and hyaluronic acid, as well as synthetic materials, such as poly(lactic-co-glycolic) acid, poly(caprolactone), and polyethylene glycol.^78,79

PRP-Loaded Scaffold in Tissue Regeneration

Wound healing

Physical, mechanical, chemical, and pathogenic damages to tissues and organs of the body are protected by the skin.⁸⁰ The body responds to skin injuries by launching a number of subtle and complex mechanisms that enable it to rebuild its integrity and restore its normal operations.⁸¹ Developing TE skin substitutes has been possible because of current advances in TE and regenerative medicine.^82,83 So, multiple forms of scaffolds (particulate, printed, porous, and fibrous) have been developed for the treatment of skin wounds, and such scaffolds have been broadly employed as skin replacements.^84–87 In spite of this, wound healing is a complex process that relies on a variety of materials to be effective. Biological base materials can recreate the ECM to fix skin damage, for instance, because vascularization is vital for wound healing. It is, however, impossible to induce enough blood vessels with a single substrate.⁸⁸ For this purpose, GF-releasing systems have been used to activate biological scaffolds with GFs before vascular growth.¹⁷ The processes of wound healing can be improved through the use of GFs and cytokines. Specific roles of GFs in wound healing are mentioned in Figure 2. Innovations based on GFs are promising for optimal wound healing because they regulate cellular behavior during wound healing processes (hemostasis, inflammation, proliferation, and remodeling).⁷² It is possible to rejuvenate the skin safely and effectively with PRP because it provides cytokines, GFs, and other biologically active substances associated with tissue regeneration and restoration.⁸⁹ Wound healing can be aided by GFs in PRP, such as EGF, PDGF, TGF-β, and VEGF.^90,91 In addition, PRP can suppress inflammation by inhibiting cytokine release. This could improve tissue healing and regeneration, stimulate the growth of new capillaries in chronic wounds, and speed up the process of epithelization. PRP also contains a few leukocytes, which synthesize ILs as part of a nonspecific immune response, bolstering the host’s defense system at the wound site via signaling proteins that attract macrophages. Several gram-positive and gram-negative bacteria have been shown to be susceptible to PRP antimicrobial activity in previous studies.⁹² Increasing matrix metalloproteinase (MMP) expression allows PRP to remodel the ECM and improve cellular proliferation and differentiation in the skin by degrading damaged ECM components. As a result of the increased secretion of hyaluronic acid, PRP makes the skin more elastic and turgid through hydration.⁹³ Although PRP poses a number of advantages, there are also potential drawbacks, such as a high risk of contamination during administration via injection, a low viability, and portability concerns. The GFs in PRP should ideally be released within 10 min. However, the majority are typically secreted over an hour. As a result, these GFs can become diluted and break down quickly once they enter the bloodstream after injection.⁹⁴ These obstacles limit the efficiency and effectiveness of platelet-based therapies. Therefore, recently, tissue-engineered constructs combined with biomaterials have been examined to develop synthetic and nonsynthetic platelet mimics to dominate these restrictions.^90,95 This integrated system, which includes platelets and biomaterials, can be delivered through multiple methods, such as topical application, intracavitary injection, or intravascular delivery to directly engage with the site of bleeding and injured tissue. These systems gradually release various GFs obtained from PRP to facilitate wound healing in a regulated way.⁹⁶ A number of research have been conducted to verify the clinical benefits of PRP-based therapies, and the majority showed that wound size could be reduced significantly without side effects. Accordingly, in the study by Amaral et al.,⁹⁷ collagen-glycosaminoglycan PRP-loaded scaffolds were used to evaluate the potential for wound healing within the skin. Research indicated that the composite scaffold emitted GFs that aid in wound healing (FGF, TGF-β) and promote vascularization (VEGF, PDGF) for a duration of up to 14 days following its implantation. Likewise, vascularization assays demonstrated increased wound healing potential by enhancing angiogenic and vascularization potential. Another study by Liu et al.⁸² examined the wound healing effect of a cocoon scaffold loaded with PRP or platelet-poor plasma. It was found that both composite materials could facilitate wound healing in vivo, but the cocoon composites combined with PRP exhibited the most effective results and were most effective. Consistent with this, Xu et al.⁸⁸ applied granule-lyophilized platelet-rich fibrin (PRF) within a polyvinyl alcohol hydrogel to treat wounds in animals. Their immunohistochemical and histological analysis revealed that the scaffold improved collagen deposition, granulation tissue formation, and the development of new blood vessels. In addition, in vivo studies indicated that these scaffolds could serve as an optimal dressing for acute full-thickness skin wounds. Table 2 provides a summary of related research on PRP-loaded scaffolds in the context of skin wound healing.

Fig. 2.

Functions of various GFs and their effect in wound healing. GF, growth factors.

Table 2.

PRP-Loaded Scaffolds in Skin Wound Healing Applications-Related Studies

Reference	Material	Form	Coculture/co-delivery	PRP type	In vivo experiments	Notes
⁹⁸	Alginate at 2.5% oxidation	Injectable	Human fibroblasts, keratinocytes	Human PRP	Diabetic wounds/mice	Along with offering mechanical support to the hydrogel, activated PRP is rich in GFs that aid in wound healing, and it also contains fibrin, which creates an optimal microenvironment for cell movement and growth.
⁹⁹	Oxidized dextran (ODEX), antimicrobial peptide-modified hyaluronic acid (HA-AMP)	Hydrogel	Antimicrobial peptides	PRP	Infected diabetic wounds/mice	It appears that ODEX/HA-AMP/PRP hydrogels with high biological activity and antibacterial properties have great capacity as wound healing accelerators.
⁹⁷	Collagen-glycosaminoglycan (collagen-GAG)	Composite scaffold	Fibroblasts, keratinocytes	Human PRP	—	PRP gel provided scaffolds with GFs that were released for up to 14 days, whereas composite scaffolds had higher mechanical properties. Comparing the released content with standard FBS culture in vitro, it was able to match, or surpass, cell proliferation in some key wound healing cells.
⁸²	Cocoon scaffold (CCSs)	Composite scaffold	—	Autologous PRP and PPP	Full-thickness skin wounds/rabbits	Both composite materials enhanced wound healing in vivo; however; CCSs + PRP showing the best results.
⁸⁸	Granule-lyophilized (G-L)-PRF/polyvinyl alcohol (PVA)	Hydrogel	—	Lyophilized PRF	Acute full-thickness skin defects/mice	In the early stages of skin repair, the G-L-PRF/PVA group exhibited low levels of inflammation, which are able to activate cell proliferation and migration, resulting in neovascularization and neotissue formation.
⁷⁴	Gelatin	Freeze-dried hydrogel sheet	—	Autologous platelet-rich plasma releasate (PRPr)	Full-thickness skin wounds/mice	The sustained-release vehicle based on gelatin impregnated with PRPr stimulates angiogenesis and accelerates skin wound repair.
¹⁰⁰	Keratin (KSO)	Hydrogels	—	Human platelet lysate (hPL)	—	The mechanical, structural, and GF release properties of hydrogels can be easily modified by changing the KSO and hPL concentrations.
¹⁰¹	Methacrylated gelatin (GelMA), methacrylated silk fibroin (SFMA)	Composite hydrogels	Adipose-derived stem cells (ADSCs)	Human PRP	Pressure ulcer/mice	In vivo wound healing experiments of mice pressure ulcers showed that GelMA/SFMA/PRP/ADSCs hydrogels could accelerate collagen synthesis, reepithelialization, and wound healing.
⁹⁵	Collagen sponge scaffolds (CSSs) modified with polydopamine (pDA)	Sponge scaffolds	—	PRP from Bama miniature pig	Full-thickness skin defects/mice	Using a composite of pDA and CSS, GFs can be released and prolonged for the treatment of full-thickness skin injuries by loading more PRP. PRP complexes were able to maintain their biological activity, promote angiogenesis, and promote cell proliferation both in vivo and in vitro.
¹⁰²	Polyhedral oligomeric silsesquioxane, poly e-caprolactone (POSS-PCL)	3D nanocomposite scaffolds	Allogenic rat ADSCs	Autologous PRP	Full-thickness skin defects/rat	Angiogenesis and tissue ingrowth were significantly higher after implanting POSS-PCL scaffolds with ADSC and PRP.
¹⁷	Lando® artificial dermal scaffold (medical silicone rubber film, bovine tendon collagen-chondroitin sulfate)	Cell-free dermal substitute	—	Autologous PRP	Skin defects/miniature pig	In addition to increasing the wound healing ability of dermal scaffolds, PRP also increased the vascularization ability of the scaffold material.
¹⁰³	Cryopreserved amnion	Decellularized scaffold	—	Autologous PRP	Burn wounds/mice	In comparison with amnion alone, scaffolds activated with PRP and calcium chloride composition demonstrated better wound adhesion.
¹⁰⁴	Type I collagen	Hydrogel scaffold	—	Fractionated PRP	Full-thickness skin defects/rat	Collagen and PRP scaffolds are capable of attracting dermal-derived stem cells and keratinocytes.
¹⁰⁵	Integra (bovine tendon collagen and chondroitin-6-sulphate and polysiloxane polymer)	Bilayer membrane scaffold	Human bone marrow-derived mesenchymal stem cells (hMSCs)	human PRP	—	As compared with those cultured on Integra matrix alone, hMSCs seeded on Integra matrix combined with PRP colonized the scaffold pores more efficiently, demonstrating a more flattened morphology and embracing the meshes of the matrix and forming a 3D cell network as a result of platelet-derived GFs.
⁹⁷	Collagen-glycosaminoglycan (collagen-GAG)/PRP gel	Porous composite scaffold	—	Human PRP	CAM assay	There was an increase in angiogenic activity and vascularization capacity of the composite scaffold in vitro, as well as the ability to support both fibroblast and keratinocyte cocultures.
¹⁰⁶	Carboxymethyl cellulose (CMC)	3D printed scaffold	—	Human PRP	Bilateral full-thickness dorsum wounds/rat	A CMC scaffold enhanced skin reepithelialization, granulation, and angiogenesis when combined with PRP in full-thickness defects.
¹⁰⁷	PRP fibrin	Injectable scaffold (IFS)	Skin fibroblasts	Autologous PRP	Full-thickness dorsum wounds/mice	IFS can accelerate wound healing in nude mice by enhancing fibroblast movement to the extracellular matrix and promoting new blood vessel formation at the wound sites.
¹⁰⁸	Carboxymethyl chitosan (CMCS), oxidized dextran (Odex), and oligomeric procyanidins (OPC)	(ROS)/pH dual responsive injectable hydrogel	—	Human PRP	Full-layer skin wounds/mice	In addition to ROS and pH sensitivity, CMCS/Odex/OPC hydrogel loaded with PRP can respond to wound microenvironments and control the release of active factors.
¹⁰⁹	Gelatin type A	Nanofibers scaffold	Human placenta-derived mesenchymal stem cells (hPDMSCs)	Autologous PRP	Diabetic foot ulcers/clinical trial	A greater reduction in wound size in the hPDMSCs/PRP gel group was obvious. This suggests that the PRP gel contributed to wound healing.
¹¹⁰	Gelatin (GLT), nanocomposites of titanium dioxide (TiO₂) (P25), single-walled carbon nanotubes (SWCNTs), Silver (Ag), and P25/reduced graphene oxide (rGO)/Ag	Hydrogel scaffold	—	Autologous PRP	Full-thickness excisional skin wounds/rabbit	P25/SWCNT/Ag and PRP were able to accelerate wound healing in comparison to GLT-loaded nanocomposites after 3 days of wound healing. Conversely, rGO-PRP treatment without GLT was not significantly different from rGO-GLT treatment without PRP.
¹¹¹	Chitosan/polyethylene glycol (CsPEG) sponge, Cs/l-arginine	Sponge-nanofibrous bilayer dressing	—	Advanced PRF	Dorsal full-thickness wound/rat	Based on the obtained results, the bilayer wound dressing utilization with the ability to release GFs and l-arginine is highly recommended to treat full-thickness wounds.
¹¹²	Oxidized chondroitin sulfate, carboxymethyl chitosan	Hydrogel scaffold	—	Human PRP	Full-thickness wounds of diabetic skins/rat	By inhibiting PRP enzymolysis as well as releasing its GFs sustainably, the hydrogel enhances cell proliferation/migration in vitro. Specifically, diabetic skin can heal full-thickness wounds much faster when granulation tissues are formed, collagen is deposited, angiogenesis is stimulated, and inflammation is reduced.
¹¹³	hyaluronic acid (HA) and ε-polylysine (ε-PLL), fibrinogen	Hydrogel scaffold	—	Autologous PRP	Full skin diabetic defects/rats	As a result of its ideal structure, excellent swelling, and hydrophilicity, as well as its good antibacterial properties, the composite hydrogel can reduce inflammation, promote angiogenesis, and promote collagen synthesis to promote wound healing.

GF, growth factor; PPP, platelet-poor plasma; PRF, platelet-rich fibrin; PVA, polyvinyl alcohol.

Bone regeneration

Interestingly, human bone has an inherent capacity for regeneration. Despite this, spontaneous healing is not possible for defects larger than a critical size. A bone’s healing process usually involves four stages that overlap each other: inflammation and vascularization, soft callus formation, hard callus formation, and bone remodeling. As such, the development and utilizing clinical translation of impressive bone regeneration modalities is helpful.^114–116 In most cases of bone deformities, bone grafting is the most prevalent procedure. The definition of a bone graft is a material implanted into the body to encourage bone regeneration.¹¹⁷ There are three major categories of bone grafts: autografts (a tissue or bone that comes from the patient), allografts (a tissue or bone from a human cadaver), and xenografts (a tissue or bone taken from an animal).¹¹⁸ Other options include biomaterials derived from synthetics and biology, tissue-engineered materials, and combinations of these materials.¹¹⁹ In the clinical setting, it is still quite common to utilize autografts and allografts for addressing substantial bone defects. However, these methods come with certain drawbacks. For example, although harvesting donor tissue for autografts, there is a risk of causing secondary injury, and with allografts, there exists the potential for pathogen transmission and immune rejection.¹²⁰ Recently, using novel biotechnology strategies and bone TE (BTE) might become an effective tool for the healing of bone defects as they are expected to overcome these shortcomings.^{118,121–124} Among the critical elements of BTE, scaffolds serve the purpose of being both a temporary substrate and a carrier of biochemical factors. In addition to providing anchorage sites, the scaffolds provide both appropriate physical stimulation (e.g., mechanical properties) and biochemical stimulation (such as cytokines and chemokines), thereby supporting cell growth and maintaining cell function.^120,125 Hence, scaffolds as grafts in bone grafting are effective in eliminating problems caused by traditional treatment. Furthermore, it is more effective in treating various diseases that damage bones.¹²⁶ A good bone regeneration scaffold should possess several essential characteristics: (1) There are four main components to biocompatibility: osteoconductivity, bioactivity, and osteoinductivity: Boosting angiogenesis and supporting normal cellular activity without toxicity; (2) biodegradability or bioresorbability: It is generally preferable to create controlled spaces for new tissue to grow into and eventually replace mature bone tissue; (3) mechanical integrity: For the bone tissue to match that of the host; and (4) interconnected pore architecture: To improve nutrient transportation and waste disposal and to direct the growth of new tissues. Because a biomaterial-based scaffold alone does not possess the intrinsic osteogenic capacity, biomimetic and functional scaffold designs have been developed and combined with GFs or osteoinductive agents to overcome these limitations.¹²⁷ It is thought that GFs control the differentiation, proliferation, and synthetic functions of bone cells, influencing the healing of fractures and the process of bone remodeling.¹²⁸ Certain GFs play a role in both the creation and healing of bone (Fig. 3). Some of these factors encourage processes that specifically lead to bone formation, such as enhancing osteoinduction, whereas others, such as VEGF and PDGF, facilitate angiogenesis and the development of new blood vessels from preexisting ones.^76,114 There are also osteoinductive GFs such as IGFs and TGFs-ß that have demonstrated great potential for regulating cell behavior in bone healing and osteogenesis, such as recruitment, migration, proliferation, adhesion, and differentiation.^129,130 Regarding this, PRP-based therapy by delivery of GFs is a promising approach to facilitate new bone formation and can be utilized as an alternative bone graft substitute. In addition, the plasma component of PRP contains proteins, such as fibrinogen, albumin, and several immunoglobulins, which play a remarkable role in bone regeneration.^131,132 Furthermore, some released cytokines by PRP also affect fracture repair such as IL-1, IL-6, and tumor necrosis factor-alpha (TNF-α).¹³³ Based on conducted studies, IL-1 and TNF-α both play a crucial role in recruiting osteoblasts to the fracture site.^134,135 In addition, IL-6 has been shown to influence callus remodeling and mineralization that significantly improves later stages of bone healing.¹³⁶ To maximize the regenerative potential of PRP-derived factors, delivery vehicles capable of releasing them over an extended period are needed because bone regeneration is a lengthy process (adequate strength can be restored within 3–6 months).¹¹⁴ To date, PRP’s use and delivery for bone regeneration have not been optimized, even though some efficacy has been demonstrated in vitro and in vivo scenarios. To overcome this limitation, several in vivo and clinical studies have evaluated the effects of PRP in combination with scaffolds as an alternative bone graft substitute. For example, Jiang et al.¹³⁷ investigated the effects of 3D-printed PRP-gelatin methacryloyl (GelMA) hydrogel scaffold on osteochondral regeneration in a rabbit model. Their findings showed that the prepared composite could accelerate osteochondral repair via immune regulation by M2 polarization and could be a potential selection for osteochondral tissue remodeling. Also, PRP-GelMA hydrogels coordinated and enhanced some overlapping osteochondral repair events, such as osteochondral differentiation, dynamic immune regulation, and chemotaxis of MSCs. In another recent study, Gan et al.¹³⁸ used a lyophilized platelet-rich fibrin (LPRFe) exudate-loaded carboxymethyl chitosan/GelMA hydrogel scaffold. In vitro tests indicated that the LPRFe-loaded hydrogel improves the adhesion, growth, movement, and bone-forming differentiation of rat bone MSCs. In addition, animal studies revealed that the hydrogel exhibited excellent biocompatibility and biodegradability, and the incorporation of LPRFe into the hydrogel can notably speed up the bone healing process, making it a potentially effective treatment for bone defects. As part of a study by Lee et al.,¹³⁹ hydroxyapatite/collagen/PRP ceramic scaffolds were used for bone tissue regeneration. This research investigated the PRP release rate over an extended cultivation period (up to 35 days). The findings revealed that the sustained release of PRP had beneficial impacts on preosteoblast cells, enhancing both their proliferation and differentiation processes. Some other PRP-loaded scaffolds that have assayed in bone regeneration have been mentioned in Table 3.

Fig. 3.

Roles of PRP components in bone regeneration.

Table 3.

Summary of Research That Used PRP-Loaded Scaffold in Bone Regeneration

Reference	Material	Scaffold form	Coculture/codelivery	PRP type	In vivo experiments	Notes
¹²⁰	Methacrylated alginate and 4-arm poly (ethylene glycol)-acrylate	Hydrogel	Mesenchymal stem cells (MSCs)	Autologous PRP	Condyle defects/rabbit	Cellular studies showed that the incorporation of PRP with biomineralization enhanced the osteogenic bioactivities and also the hydrogel biocompatibility was prompted. In addition, the animal assays demonstrated this biomineralized PRP-hydrogels could significantly accelerate bone repair.
¹³⁰	Decellularized omentum	Decellularized scaffold	—	Autologous PRP	Critical-sized bone defects/rat	This research results exhibited this decellularized omentum scaffold is suitable for critical-sized bone injuries.
¹²⁵	Poly(ε) caprolactone and β-tricalcium phosphate (PCL-TCP)	Composite scaffold	Human umbilical cord-derived MSCs (hUCMSCs)	CaCl₂-activated autologous PRP	Mandibular bony defects/miniature pig	The obtained results of this study suggested PCL-TCP scaffold is helpful for bone remodeling in bone defects surrounding dental implants.
¹⁴⁰	Decellularized bone matrix (DBM)	Decellularized scaffolds	—	Autologous PRP	Critical-sized radial defects/rabbits	The novel composite of DBMs loaded with PRP can be utilized as a promising bone regeneration construct.
¹⁴¹	Collagen	Sponge scaffold	—	Autologous PRP	Critical-sized defect of the tibia/sheep	The research indicated that PRP was ineffective in promoting bone repair in critical-sized defects that have a limited ability to regenerate.
¹⁴²	Collagen-hydroxyapatite	Nanocomposite scaffold	—	CaCl₂-activated autologous PRP	Osteochondral defects/sheep	The hydroxyapatite-collagen scaffold facilitated the healing of osteochondral lesions, but adding platelet GFs did not enhance the outcome.
¹⁴³	Allogeneic cancellous bone granules	Lyophilized granule composite scaffolds	Bone marrow-derived MSCs	Autologous PRP	Critical-sized segmental bone defects/rabbit	In this study, the combination of the prepared structure and PRP did not show a significant difference in bone healing compared with the contralateral control within the same animal.
¹⁴⁴	Bilayer gelatin/β-tricalcium phosphate sponges loaded with mesenchymal stem cells, chondrocytes, bone morphogenetic protein-2, and platelet rich plasma (Ch/MSC/PRP/GT)	Freeze-dried sponges scaffold	MSCs, chondrocytes, bone morphogenetic protein-2	Autologous PRP	Osteochondral defects of the talus/horse	The results of this study showed that bilayer scaffolds made up of Ch/MSC/PRP/GT for the chondrogenic layer and MSC/BMP2/GT for the osteogenic layer improved osteochondral repair in a horse model.
¹⁴⁵	Hyaluronic acid/gelatin-biphasic calcium phosphate (BCP)	Freeze-dried hydrogel scaffold	—	Autologous PRP	Calvarial defect/rats	Cellular assays indicated that the PRP-loaded scaffold exhibited greater cell count, proliferation, and survival. However, in vivo results demonstrated that the PRP scaffold did not outperform the scaffold without PRP.
¹³⁹	Calcium-deficient hydroxyapatite, collagen	3D printed scaffold	—	Human PRP	—	PRP composite has potential for the use as an excellent bioactive scaffold for bone tissue repair.
¹⁴⁶	Nano-calcium sulfate(nCS), alginate	Sandwich-like scaffold	BMP2 gene-modified MSCs	Autologous PRP	Critical-sized calvarial defects/rat	The use of BMP2-modified MSCs along with the nCS/PRP scaffold greatly enhanced new bone formation in comparison to the groups that did not include PRP and/or BMP2.
¹⁴⁷	Poly(lactic-co-glycolic acid) (PLGA)	Porous scaffold	Leukocyte	Autologous L-PRF	Mandibular defects/sheep	The use of PLGA scaffolds along with the localized administration of autologous L-PRF exudate resulted in significant bone healing.
¹⁴⁸	Oyster shell (OS), alpha-calcium, sulfate hemihydrate (α-CSH)	Composite scaffold	BMSCs	Autologous PRP	Calvarial defects/rat	The scaffold created using OS, α-CSH, PRP, and implanted with BMSCs may be clinically appropriate and offer benefits as a ready-to-use, cell-loaded option for treating critical-sized calvarial bone defects.
¹⁴⁹	Chitosan (CS)–hydroxyapatite	Composite scaffold	—	Lyophilized platelet-rich fibrin (L-PRF)	—	It was shown that the release duration of GFs from L-PRF was significantly extended, with GFs still being detectable even after 35 days of continuous release.
¹⁵⁰	Chitosan	porous sponges Scaffold	—	P-PRP (activated P-PRP [aP-PRP] by adding autologous serum CaCl₂ solution as agonists)	—	The composite scaffolds outperformed aP-PRP on its own, indicating that the porous chitosan helped stabilize the fibrin network. Additionally, it was observed that the concentration of chitosan and the freezing process influenced the physicochemical and biological characteristics of the scaffolds.
¹⁵¹	Chitosan-gelatin/nano-hydroxyapatite (CS–G/nHA)	Porous composite scaffolds	Fibrin glue (FG)	Human PRP	—	The scaffolds that were prepared and infused with FG and a-PRP exhibited a fibrin network on the surface of the composite scaffold, which enhanced the mineralization and osteoblastic differentiation of the collected cells.
¹⁵²	PRP mixed with CaCl₂	PRP gel	—	Human PRP	—	The findings of this research showed that the cell shape, viability, and proliferation were influenced by culturing on PRP scaffolds made with varying concentrations of CaCl₂, leading to a range of biological and physical properties in the scaffolds.
¹⁵³	PCL/chitosan	Core–shell nanofibrous scaffold	—	Homogenized PRF	—	The integration of PRF with a PCL/CS scaffold resulted in a reduction of fiber diameter and swelling ratio while increasing porosity, wettability, and the degradation rate of the PCL/CS-PRF core–shell nanofibrous structure.
¹⁵⁴	Macroporous calcium phosphate cement (CPC)	Macroporous scaffold	Autologous bone marrow MSCs (BMSCs)	Autologous PRP	Femoral condyle defect/Tibet minipig	CPC scaffold contains of autologous BMSC-PRP promoted the bone repairing and blood vessel density in minipigs, in comparison with CPC control.
¹⁵⁵	Beta-tricalcium phosphate (b-TCP)	Porous scaffold	Recombinant human bone morphogenetic protein-2 (rhBMP-2)	Autologous PRP	Nonthrough cranial bone defect/rabbit	Bone restoring dramatically enhanced with the addition of rhBMP-2, but the addition of PRP was not effective.
¹⁵⁶	Hyaluronic acid-g-chitosan-g-poly(N-isopropylacrylamide) (HA-CPN), biphasic calcium phosphate (BCP) ceramic microparticles	Thermo-gelling hydrogel	Rabbit adipose-derived stem cells (rASCs)	Autologous PRP	Critical-sized calvarial bone defect/rabbits	The HA-CPN scaffold enhanced with PRP/BCP, which serve as osteoinductive and osteoconductive agents, demonstrated the ability to provide synergistic signals that promote the osteogenesis of rASCs in both in vitro and in vivo assays.
¹⁵⁷	Poly(ether) sulfone (PES), poly(vinyl) alcohol (PVA)	Co-electrospun composite scaffolds	—	Human PRP	—	Combination of PRP with electrospun PES/PVA scaffold had a positive effect on osteogenic differentiation of adipose derived mesenchymal stem cells (AdMSCs).
¹⁵⁸	PRP	PRP gel	Bone marrow stromal cells (BMSCs)	Autologous PRP	Full-thickness calvarial defects/rabbits	The use of PRP as an autologous scaffold resulted in greater bone formation from dexamethasone-induced BMSCs compared with uninduced BMSCs, indicating that the inductive potential of PRP was somewhat restricted.
¹⁵⁹	Alginate	Hydrogel	Muscle satellite cells (MSCs)	Sprague-Dawley rats PRP	Subcutaneous pockets/nude mice	MSCs activated by PRP contained within an alginate gel blend can be induced to develop into an osteoblastic phenotype, both in vitro and in vivo.
¹⁶⁰	Medical grade Polycaprolactone-Tricalciumphosphate (mPCL-TCP)	Composite scaffolds	—	rhBMP-7 delivered in PRP	Mid-diaphyseal tibial segmental defect/sheep	The findings indicated that the dosage used in conjunction with PRP is insufficient to reliably heal a large tibial injury. In addition, there was no evidence of functional recovery in bone properties or new bone formation at later stages.
¹⁶¹	Borosilicate, bioactive glass	Three-dimensional porous scaffolds	—	Autologous PRP	Non-critical-sized defects in the femoral head/rabbit	Loading the prepared scaffolds with PRP increased bone healing in the segmental defects in comparison with the scaffolds without PRP.
¹⁶²	Silicon stabilized, hydroxyapatite, tricalcium phosphate	Composite scaffolds	—	Allogeneic PRP gel	Calvarial defect/rabbit	The introduction of PRP influenced the local tissue microenvironment by supplying essential hidden factors for repair, which in turn encouraged the recruitment of progenitor cells, the deposition of collagen and bone matrix, and established a connection between the scaffold and the bone.
¹⁶³	Calcium aluminate (CA)	Scaffold disks	Melatonin	Autologous PRP	Critical-sized calvarial defects/rat	Combination of PRP with CA-Mel scaffolds did not promote bone healing compared with CA-Mel alone.
¹⁶⁴	Collagen (Co), powder-mixed hydroxyapatite (HA)	Hydrogels	Rabbit BMMSCs	Autologous PRP	Full-thickness critical size bone defect/rabbit	HA/Co nanocomposite seeded with MSC and loaded with PRP can stimulate osteoblastic production of osteocalcin protein, which leads to accelerated bone remodeling.
¹⁶⁵	Polylactic acid-gelatin-nano-hydroxyapatite (PLA/G-nHA)	3D-printed scaffolds	—	Autologous PRP	Critical-sized calvaria defect/rat	The PLA/G-nHA/PRP was shown to enhance cell proliferation, cell adhesion, and mineralization.

Cartilage repair

Cartilage defects resulting from various causes such as illness or injury remain a significant challenge for surgeons due to the cartilage tissue’s limited ability to heal.¹⁶⁶ When the cartilage of the joint is damaged, the joint’s structure and function will be affected. A failure to treat it in time will result in joint pain and movement issues. In large defects, cartilage’s self-repair capacity is limited due to its low vascularity and restricted number of chondrocytes with weakened proliferation and migration.¹⁶⁷ Within the past decade, several techniques for treating cartilage defects have been developed. The use of cell-based therapies (autologous chondrocytes, matrix-induced autologous chondrocytes, bone marrow stem cells, adipose stem cells, microfracture, and cytokines) to repair cartilage can facilitate this process. Despite these efforts, it has not been possible to regenerate hyaline cartilage with similar morphology in these cases.¹⁶⁸ In recent years, TE has emerged as a promising approach for addressing cartilage defects.^169,170 In the 1990s, advances in scaffold materials aligned with the progress made in GFs for cartilage TE. Scaffolds show promise as a feasible surgical solution for cartilage repair. As a result, the development of methods that combine scaffolds and GFs is still a burgeoning field of study at the moment. In general, in the field of cartilage regeneration, some GFs, such as IGF-I, bFGF, HGF, PDGF, and the TGF-β superfamily, are among the GFs whose research has recently received the most attention. In Figure 4, the commonly related GFs involved in cartilage repair and their function are illustrated.¹⁷¹ Currently in research related to repairing cartilage, PRP is gaining recognition as a biological method for supplying elevated levels of GFs and cytokines to the location of injury. Furthermore, the fibrinogen present in platelet-rich plasma has the potential to become active and create a fibrin matrix fills in cartilage lesions and meets the necessary conditions for natural wound healing. PRP has been widely utilized in orthopedic injury-related diseases due to its ability to decrease inflammation, enhance angiogenesis, and stimulate the growth and specialization of cartilage cells, ultimately aiding in the healing process of bone and cartilage injuries.¹⁷⁰ Also, it has been found that cartilage healing via PRP therapy may reduce IL-1β-induced inhibition of type II collagen and aggrecan, as well as increase their protein levels.¹⁷² In addition, studies have shown that PRP could decrease the raised level of nitric oxide, which induces chondrocyte apoptosis, increases the production of MMPs, and suppresses collagen synthesis, causing cartilage degradation.^173–175 Furthermore, it may also restore self-renewal capacity and alter quiescence in aging cartilage by inducing chondrocyte autophagy, which could reinstate the regenerative process of cartilage.¹⁷⁶ PRP also includes various plasma proteins, which play essential roles in the repair process of connective tissues.¹⁷⁷ Although PRP has achieved success in treating articular cartilage injury, there is still debate surrounding its mechanism of action, effectiveness in clinical treatment, and preparation method due to its complicated composition.¹⁷⁸ So far in various studies, both forms of uninjectable (solid scaffolds) and injectable constructs containing PRP have been used, and their cartilage repair potency was investigated.¹⁶⁷ The scaffold utilized for cartilage TE must be made from materials that are both biocompatible and biodegradable, capable of offering sufficient mechanical stability throughout the regeneration process, and able to support articulate contact. Polymers and decellularized ECM are the top choices for scaffold preparation in cartilage TE.¹⁷⁹ The influence of platelet-derived GFs on chondrogenesis has been studied through both in vitro and in vivo models to understand their role in cartilage development. In a study, Lee et al.¹⁸⁰ evaluated the regenerative abilities of PRP when combined with a composite scaffold made of chondrocytes/hydrogel [gelatin-poly (ethylene glycol)-tyramine] in treating articular cartilage defects in a rabbit model. Their findings showed that using a PRP-containing hydrogel scaffold can improve the development and preservation of hyaline cartilage characteristics in articular cartilage defects when implanted. In addition, the results indicated that the continuous release of GFs from PRP in hydrogels improves the regeneration of hyaline chondrocytes and the formation of perichondrium-like normal joint cartilage by upregulation of CB1 and CB2. In a research conducted by Maria Sancho-Tello et al.,¹⁸¹ the advantages of using activated PRP along with a stabilized porous chitosan scaffold for cartilage regeneration were assessed. The activated PRP-loaded scaffold showed a significant increase in cell count compared with the stabilized porous chitosan scaffolds. Chondrocytes grown on the stable porous chitosan exhibited higher levels of type I collagen, whereas type II collagen was not observed. In contrast, cells cultured on activated PRP-loaded porous chitosan scaffolds showed high levels of type II collagen and low levels of type I collagen. To sum up, activated PRP boosts cell clustering and promotes the development of cartilage cells grown on stable porous chitosan scaffolds. Some other related studies are listed in Table 4.

Fig. 4.

PRP-related GFs and their mechanism in cartilage repair.

Table 4.

Example of PRP-Loaded Scaffold Application in Cartilage Repair

Reference	Material	Form	Coculture/codelivery	PRP type	In vivo experiments	Notes
¹⁸²	PRP gel	—	MSCs from bone marrow and adipose tissue	Autologous PRP	Osteochondral defects/rabbits	Research results indicate that PRP is a potential bioactive scaffold capable of releasing endogenous GFs and promoting the differentiation of BMSCs and ADSCs into chondrocytes.
¹⁸³	PLGA	Bilayer scaffold	—	Autologous PRP	Osteochondral defects/rabbits	Osteochondral defect in the rabbit model was significantly repaired using bilayer autologous PRP and PLGA scaffolds.
¹⁸⁴	Agarose	Hydrogel scaffold	Porcine chondrocytes	Autologous PRP	Cartilage explant (articular cartilage was aseptically cut from the femoropatellar joints of mini pigs)	Combination of PRP and agarose gel promoted chondrocyte differentiation, proliferation, and integration between native cartilage and engineered tissue.
¹⁸⁵	Polyurethane, PRP fibrin	Composite scaffold	Chondrocytes	PRP from New Zealand white rabbits	Dorsal subcutaneous space/nude mice	It was found that this composite promoted chondrocyte proliferation, increased aggrecan expression and type II collagen gene expression, improved cell distribution and density, increased the content of new GAGs, and led to a better cartilaginous tissue production.
¹⁸⁶	PRP fibrin	Hydrogel scaffold	Chondroprogenitors	Human allogeneic PRP	—	The synergistic effect of PRP in supporting cell proliferation, maintaining cell viability, and favoring extracellular matrix synthesis makes it a promising bioactive scaffold.
¹⁶⁸	Hyaluronic acid	Hydrogel scaffold	Leukocyte	Human L-PRF and L-PRP	Explant model (osteochondral plugs bovine femoral condyle and trochlea)	There was no obvious difference between L-PRF and L-PRP in biomechanical strength of healing cartilage, which suggests that both may be beneficial in improving cartilage strength through different mechanisms.
¹⁸⁷	Polyglycolic acid (PGA)–hyaluronan	Cell-free scaffold	—	Autologous PRP	Patients with arthroscopic implantation	Combination of PGA-hyaluronan scaffold and PRP results in cartilage repair and improvement in patient-reported outcomes.
¹⁸⁸	Collagen type I	3D scaffold	Human recombinant insulin	Autologous PRP	—	The differentiation of ASCs into chondrocytes and osteoblasts is facilitated by 3D collagen scaffold culture in conjunction with platelet-derived GFs and insulin.
¹⁸⁹	Silk fibroin	3D scaffold	Human adipose-derived stem cells (ADSCs)	Human allogeneic PRP	—	Cellular study showed ADSC-SS supplemented with 10% PRP medium supported ADSC chondrogenesis effectively.
¹⁹⁰	Hyaluronic acid (HA) derivative, human fibrin glue (FG)	Membrane scaffold	Autologous cartilage fragments	Autologous PRP	Trochlear osteochondral defects/rabbit	The use of autologous cartilage fragments loaded onto HA felt/FG/PRP scaffolds improved the repair process for rabbit osteochondral defects.
¹⁹¹	PLGA	Flexible mesh scaffold	Human articular chondrocytes	Allogenic leukocyte-depleted PRP	Meniscus disc explants in subcutaneous pouches/nude mice	In vivo, PRP pretreatment of PLGA scaffolds results in a similar healing capacity as cell-seeded scaffolds.
¹⁹²	Polyglycolide–hyaluronan (PGA-HA)	Composite scaffold	Multipotent human subchondral progenitor cells	Human PRP	—	Progenitor cells derived from PGA-HA scaffolds are differentiated into chondrogenic cells through PRP, which may benefit stem and progenitor cell-based cartilage repair procedures.
¹⁹³	PGA-fibrin	PGA scaffolds	Infant articular hip chondrocytes	Human PRP	Subcutaneous implantation/athymic mice	Incorporating PRP into expanded hip cartilage cultures, which include mature cartilage cells and undifferentiated or immature mesenchymal cells, could enhance cartilage development in vivo by promoting the differentiation of immature cells and/or encouraging chondrogenesis in the expanded hip chondrocytes.
¹⁹⁴	Cancellous bone autograft, PRP	Autograft	—	Autologous PRP	Hepple stage V osteochondral lesions of the talus (OLTs)/clinical trial	Combined PRP scaffolds with cancellous bone autografts may improve cartilage and subchondral bone regeneration in Hepple stage V OLTs.
¹⁹⁵	PLGA	Nanofiber scaffold	Stromal vascular fraction (SVF)	Autologous PRP	Osteochondral defect in medial femoral condyle/dogs	In comparison to knees treated with SVF, PRP treatment led to better lameness scores and objective kinetic evaluations of function; however, there were no statistically significant enhancements in function, cartilage composition, or histological findings.
¹⁹⁶	Decellularized cartilage graft	3D composite scaffold	Chondrocytes	Autologous PRP/thrombin gels	Full-thickness osteochondral defects/mini pigs	The application of PRP led to a rise in the expression of chondrogenic markers in both in vitro and in vivo cartilage regeneration.
¹⁹⁷	Alginate	Hydrogel scaffold	Adipose mesenchymal stem cells (ADSCs)	Allogeneic PRP	Osteochondral lesion/rabbit	Scaffold loaded with ADSCs and supplemented with PRP-induced chondrogenic marker expression, induced ECM secretion compatible with natural hyaline cartilage, and enhanced regeneration integrity.
¹⁹⁸	Silk fibroin (SF)—spidroin	Composite scaffold	l‐ascorbic acid	PRP	—	With PRP added, the scaffold containing 10% silk ppidroin provides a better surface for cell attachment, an important early step for cell differentiation, proliferation, and survival.
¹⁹⁹	Sodium alginate (SA), chitosan (CH)/chondroitin sulfate (CS)/SF	Hydrogel porous 3D scaffold	Chondrocyte	Autologous PRP	Full-thickness articular cartilage defect/rabbit	Hybrid matrix embedded with SA/PRP loaded with chondrocytes facilitated the deposition of hyaline matrix and showed superior integration potential with native cartilage.
²⁰⁰	PLGA, PRP hydrogel	Hybrid scaffold	MSCs	Autologous PRP	Osteochondral defects/rabbit	The PRP hydrogel induced a higher proliferation and differentiation rate of MSCs than the control.
²⁰¹	Sodium alginate, platelet lysate-rich plasma (PLP)	Hydrogel scaffold	—	Human PRP, autologous PRP	Cartilage defect/rabbit	By modulating the anti-inflammatory microenvironment, platelet lysate-rich plasma macroporous hydrogel (PLPMH) scaffold treatment enhanced cartilage structural integrity.
²⁰²	PRP gel (APG)	Hydrogel scaffold	Chondrocyte	Autologous PRP	Subcutaneous implantation/nude mice	APG scaffolds provide a high level of GFs that can efficiently stimulate the proliferation of chondrocytes.
²⁰³	Autologous PRF	Membrane scaffold	BMSCs	New Zealand rabbit PRP	Ectopic transplantation/nude mice	BMSC/PRF tissue-engineered cartilage transplants that are pretreated for chondrogenic differentiation are able to maximize seed cell differentiation potential.
¹³⁷	Gelatin methacryloyl (GelMA)	Hydrogel scaffold		Autologous Lr-PRP (leukocyte-rich PRP)	Osteochondral defects/rabbit	As a result of facilitating MSC proliferation and differentiation, the PRP could significantly promote tissue repair.
²⁰⁴	Silk fibroin (SF)	3D-printed scaffold	Chondrocytes	Autologous PRP	—	Integrating PRP into SF-based bioinks can sustain the release of self-derived GFs. The 3D-printed SF-PRP scaffold showed enhanced biological effectiveness.

ECM, extracellular matrix.

Future Prospect of PRP Therapy

Although considerable basic science research combined the effect of PRP and TE, wide variability in the preparation of platelets and lack of standard reporting makes it difficult to elucidate the efficacy of PRP in regenerative medicine; therefore, validated platelet preparation methodologies are essential for future clinical trials. Advances in the development of biomaterials have opened new avenues for the delivery of platelets. It should be considered that long-term storage and simple incorporation of PRP in TE scaffolds could significantly help clinical applications as on-site preparation of scaffolds adds cost and complexity. Although the prospects remain promising, robust and long-term clinical trials for using PRP in TE are essential to help translate these results to clinical practice.

Conclusions

Despite the promising potential of GFs in tissue regeneration, their utilization in clinical settings has been restricted due to their short biological half-life, fast degradation, high cost, and severe side effects under physiological conditions. Platelets store GFs and are essential for many important bodily functions, such as healing damaged tissue. Therefore, an alternative method for delivering concentrated GFs to the site of healing is through the utilization of PRP. The PRP is composed of plasma that has higher than normal levels of platelets, making it a promising option for regenerative medicine treatments for a range of conditions, such as musculoskeletal injuries and chronic wounds. PRP can be combined with a carrier to improve its effectiveness in healing and regenerating tissues, as well as enhancing the availability of GFs by utilizing a controlled release approach. The perfect release mechanism should enable the release of multiple factors and, most importantly, should be able to synchronize the timing of releasing factors derived from PRP with those needed for tissue regeneration. In terms of this issue, transport mechanisms utilizing biological and synthetic polymer scaffolds have proven effective in numerous medical uses. In this review, the application of PRP-loaded scaffold in soft and hard tissue regeneration, including skin, bone, and cartilage, was discussed in detail.

Footnotes

Authors’ Contribution

Conceptualization: N.K-N., R.K.O., and A.S.; Writing—original draft: N.K-N., B.T., and B.A.; Writing—review & editing: T.M., R.K O., and A.S.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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