Advances with Platelet-Rich Plasma for Bone Healing

Figures & data

Table 1 Function of the Growth Factors and Cytokines Found in PRP on Bone Regeneration

Category	Factors	Roles and Function
Inflammatory Cytokines	Interleukin-1 (IL-1)	Initiates inflammation, recruits immune cells, and triggers cellular responses.
	Interleukin-6 (IL-6)	Involved in callus remodeling and mineralization, recruit’s osteoblasts.
	Tumor Necrosis Factor-alpha (TNF-a)	Recruit’s osteoblasts and plays a pivotal role in bone formation.
Growth Factors	Platelet-Derived Growth Factor (PDGF)	Stimulates revascularization, collagen synthesis, and bone regeneration.
	Transforming Growth Factor-beta (TGF-B)	Initiates signaling pathways in osteoprogenitor cells and supports long-term healing, bone regeneration, and remodeling.
	Insulin-Like Growth Factor-1 (IGF-1)	Influences osteoblasts and pre-osteoblasts, inhibits apoptosis, and enhances collagen synthesis and osteogenesis.
Angiogenic Factors	Vascular Endothelial Growth Factor (VEGF)	Stimulates angiogenesis, recruits endothelial cells, and supports oxygen and nutrient delivery.
	Angiogenin	Contributes to the development of collateral circulation, enhancing blood supply redundancy.
Other Bioactive Factors	Serotonin, Histamine, and Dopamine	Increases capillary permeability, facilitating the influx of inflammatory cells.
	Calcium	Promotes the formation of a stable fibrin clot.
	Adenosine	Mitigates excessive inflammation and tissue damage.

Figure 1 Density Gradients of Cells Contained within Blood Aspirate.

Notes: (A) Platelets, (B) Monocytes, (C) Lymphocytes, (D) Basophils, (E) Neutrophils, (F) Erythrocytes, (G) Eosinophils.

Figure 2 (A) Plasma-Based PRP Preparation. (B) Buffy Coat-Based PRP Preparation.

Table 2 Effects of PRP on Cell Behavior in vitro

Author (Year)	Cell Type(s) Used	Control Group(s)	PRP Effect on Cells
Kinoshita et al (2020)^Citation31	Human osteoblasts	Cell media only	Fresh and freeze-dried PRP increased osteoblast proliferation
Kanno et al (2004)^Citation129	Human osteosarcoma cell lines HOS and SaOS-2	Cell media only	PRP increases HOS and SaOS-2 proliferation in dose-dependent manner
Fernandez-Medina et al (2019)^Citation72	Human osteoblasts	Thrombus (clot)	Reduced cell viability and migration above concentrations of 60%
Ferreira et al (2005)^Citation142	Human osteoblasts	None	PRP increases osteoblast proliferation in dose-dependent manner up to 50% concentration
Steller et al (2019)^Citation143	Osteoblasts and oral fibroblasts	Cell media only	PRP and PRF increased proliferation and migration of osteoblasts and fibroblasts, counteracting the negative effects of zoledronic acid
Ogino et al (2016)^Citation144	Human osteosarcoma cell line SaOS-2	Platelet poor plasma (PPP)	PRP increases cell proliferation in dose-dependent manner
Vahabi et al (2019)^Citation45	MG-63 osteoblast-like cells and human fibroblasts	Cell media only	PRP increases viability and adhesion of osteoblast like cells and fibroblasts
Celotti et al (2015)^Citation146	Human osteosarcoma cell line SaOS-2	Cell media only	PRP increases cell proliferation and migration in dose-dependent manner
Wang et al (2018)^Citation147	Human osteoblasts	Cell media only	iPRF more so than PRP, promoted osteoblast proliferation and migration
Graziani et al (2006)^Citation61	Human osteoblasts and fibroblasts	Cell media only	PRP increases cell proliferation of both osteoblasts and fibroblasts in dose dependent manner up to 50% concentration above which caused reduced cell proliferation
Vahabi et al (2017)^Citation130	MG-63 osteoblast-like cells and human fibroblasts	Cell media only	PRP did not show significant increase in cell proliferation
Casati et al (2015)^Citation30	Human osteosarcoma cell line SaOS-2	Cell media only	PRP stimulates cell migration
Slapnicka et al (2008)^Citation131	Human osteoblasts	Cell media only	PRP did not significantly increase cell proliferation
Martinotti et al (2014)^Citation132	Human osteosarcoma cell line SaOS-2	Cell media only	PRP promotes cell migration and induces a mixed osteoclastic/osteogenic gene expression
Gaßling et al (2009)^Citation133	Human osteosarcoma cell line SaOS-2, human osteoblasts, and human fibroblasts	Cell media only	PRP led to increased growth factor secretion compared to PRF
Herrera et al (2012)^Citation134	Human osteosarcoma cell line SaOS-2	Cell media only	PRP increases osteoblast activity and cytokine release
He et al (2009)^Citation135	Rat osteoblasts	Cell media only	PRF led to gradual and sustained release of cytokines compared to PRP
Mazzocca et al (2012)^Citation136	Human osteocytes, myocytes, and tenocytes	Cell media only	All forms of PRP increased cell proliferation of all cell types
Mooren et al (2010)^Citation137	Rat osteoblast-like cells and human umbilical vein endothelial cells (HUVECs)	Cell media only	PRP promotes proliferation of osteoblast-like cells and promotes tubular formation in endothelial cells in a dose-dependent manner
Garcia-Martinez et al (2012)^Citation138	Human osteoblasts	Cell media only	PRP increases cell proliferation and altered expression of cell-surface markers
Zou et al (2014)^Citation140	Rabbit bone marrow mesenchymal stem cells (BMSCs)	Cell media only	PRP can promote proliferation and osteogenic differentiation of BMSCs
Bi et al (2010)^Citation139	Goat marrow stromal cells (MSCs)	Cell media only	Cell growth and alkaline phosphatase activity greater on the TCP+PRP composite compared to TCP and cell media alone control.
Chen et al (2013)^Citation67	Rate Bone marrow mesenchymal stem cells (BmMSCs)	Cell media only	Greater cell proliferation in high and medium concentration PRP. Higher alkaline phosphatase activity in low and medium concentration PRP, but inhibited activity in high concentration PRP.
Qi et al (2015)^Citation141	Bone marrow mesenchymal stem cells (BmMSCs)	Cell media only	Increased expression of collagen I, collagen III, tenomodulin, and osteocalcin genes, increased alizarin red staining, and increased alkaline phosphatase activity in PRP group suggestive of ability of PRP to promote osteogenic differentiation

Table 3 Effects of PRP on Bone Healing in Pre-Clinical in vivo Animal Models

Author (Year)	Animal Model (Bone)	Scaffold Used	PRP Group(s)	Control Group(s)	Endpoint	Blinded Evaluation?	Radiographic Outcome	Histopathologic Outcome	Biomechanical Outcome
Rai et al (2007)^Citation164	Rat (femur)	Polycaprolactone tricalcium phosphate (PCL-TCP)	PCL-TCP + PRP	PCL-TCP	12 weeks	X-rays	Increased bone formation in PRP group by x-ray and micro-CT	Similar qualitative outcomes between PRP group and control group	PRP group stiffer but no difference in yield and maximum torque
Cho et al (2013)^Citation177	Dog (tibia)	None	PRP	Untreated	16 weeks	None	Bone activity index on nuclear scan greater at 4 weeks in PRP group, but less in PRP group at weeks 8, 12, and 16	Bone-to-implant contact (BIC) was higher for the PRP group	None
Dallari et al (2006)^Citation178	Rabbit (femur)	Freeze-dried bone allograft (FDBA)	PRP Bone marrow stromal cells (BMSCs)+PRP FDBA+PRP BMSCs+FDBA+PRP	Untreated	12 weeks	Histology	None	Increased bone healing in all experimental groups compared to control. Increased bone healing in FDBA+PRP, and BMSCs+FDBA+PRP compared to PRP alone	None
Guzel et al (2015)^Citation196	Rat (femur)	None	PRP	Untreated	9 weeks	Histology and biomechanics	None	Increased bone healing in the PRP group	Higher ultimate failure load in PRP group
Hakimi et al (2010)^Citation197	Mini pig (tibia)	Autologous bone graft	Autologous bone graft+PRP	Autologous bone graft	6 weeks	None	Similar rates of osseous bridging on x-rays	Superior bone formation in central and cortical defect zone in PRP group	None
Hokugo et al (2005)^Citation123	Rabbit (ulnar)	Gelatin hydrogel	Gelatin Hydrogel+PRP Fibrin+PRP PRP	Gelatin hydrogel Untreated	4 weeks	None	Greatest rate of bone healing in Gelatin hydrogel+PRP group followed by the Fibrin+PRP group	Greatest rate of bone healing in Gelatin hydrogel+PRP group followed by the Fibrin+PRP group	None
Jungbluth et al (2010)^Citation198	Mini pig (tibia)	Calcium phosphate granules (CPG)	CPG+PRP	CPG	6 weeks	X-rays	Semi-quantitative analysis showed slightly more osseous bridging in PRP group	Greater new bone formation in PRP group in central and cortical defect zones	None
Kanthan et al (2011)^Citation150	Rabbit (tibia)	Artificial bone graft (ABG)	ABG+PRP PRP	ABG Untreated	11 weeks	X-rays	Greatest healing in ABG+PRP group compared to all other groups. PRP alone better than untreated control but no different to ABG alone	Greatest healing in ABG+PRP group. ABG better healing than control. PRP did NOT have better histologic healing than untreated control.	None
Kasten et al (2008)^Citation151	Rabbit (radius)	Calcium-deficient hydroxyapatite ceramic scaffold (CDHA)	CDHA+PRP CDHA+PRP+mesenchymal stem cells (MSCs)	CDHA Untreated	16 weeks	None	Bone formation greater in CDHA+PRP and CDHA+PRP+MSC groups compared to CDHA alone, as measured by micro-CT	Bone formation greater in CDHA+PRP and CDHA+PRP+MSC groups compared to CDHA alone	All test groups were stiffer than untreated control. No difference in stiffness between test groups
Kroese-Deutamn et al (2008)^Citation152	Rabbit (radius)	Titanium fiber mesh (TFM)	TFM+autologous bone+PRP TFM autologous bone	TFM	12 weeks	None	Bone healing seen in all test groups but not in all control groups	Greater bone formation in TFM+autologous bone+PRP than all other groups	None
Kurikchy et al (2013)^Citation153	Rabbit (femur)	Xenogeneic bone graft (XBG)	XBG+PRP	XFG Untreated	4 weeks	None	None	Increased number of osteocytes, osteon diameter, and lamellar thickness in XBG+PRP groups compared to all other groups	None
Lin et al (2013)^Citation154	Rabbit (femur)	Nanohydroxyapatite-type I collagen beads (CIB)	CIB+BMSCs+PRP CIB+PRP PRP+BMSCs PRP	Untreated	8 weeks	Histology	Greater bone healing in all experimental groups compared to untreated control as assessed on micro-CT	Increased bone formation in CIB+BMSCs+PRP and PRP+BMSCs groups	None
Lysiak et al (2008)^Citation155	Rabbit (femur)	Collagen	Collagen+PRP	Untreated	12 weeks	None	None	Greater bone formation in experimental groups compared to control group	None
Malhotra et al (2014)^Citation156	Sheep (tibia)	Biphasic calcium phosphate (BCP)	BCP+PRP	BCP Untreated	4 weeks	X-ray and histology	Greater bone healing in BCP+PRP compared to all other groups via micro-CT Greater bone healing in BCP+PRP group compared to untreated but no different to BCP alone on x-ray.	Greater bone formation in BCP+PRP compared to BCP alone and untreated control.	None
Manitha et al (2009)^Citation158	Goat (femur)	Tri-phasic ceramic-coated hydroxyapatite (HASi)	HASi+BMSCs+PRP	HASi	8 weeks	None	Greater bone formation in the experimental group compared to HASi alone	No significant difference in bone formation between all groups	None
Niemeyer et al (2010)^Citation160	Sheep (tibia)	Collagen sponges (CS)	CS+Adipose-tissue derived stems cells (ASCs)+PRP	CS	26 weeks	None	No significant difference in bone formation between test group and control assessed on x-ray	No significant difference in bone formation between test group and control assessed on histology	None
Parizi et al (2012)^Citation162	Rabbit (radius)	Coral	Coral+PRP	Coral Untreated	8 weeks	Gross evaluation	Improved bone healing in the coral and coral+PRP groups compared to untreated control	Improved bone healing in the coral and coral+PRP groups compared to untreated control	PRP with coral group had higher ultimate load than the negative control group, whereas coral group alone did not
Simman et al (2008)^Citation166	Rat (femur)	None	PRP	Untreated	4 weeks	Fully blinded analysis	Higher callus to cortex width ratio in PRP group	No difference in BMP2 or total TGF-B expression between the groups	Increased strength in PRP group
Souza et al (2012)^Citation167	Dog (radius)	None	PRP	Untreated	8 weeks	Fully blinded analysis	Greater healing in the PRP group	PRP group showed new bone formation superior to control group	None
Sugimori et al (2006)^Citation168	Rat (tibia)	Apatite foam (AF)	AF+PRP PRP	AF Untreated	12 weeks	None	None	AF+PRP has more bone formation than all other groups	None
Zhang et al (2013)^Citation169	Rabbit (radius)	Deproteinized bone matrix (DBM)	DBM+PR DBM+PRP+MSCs	DBM	12 weeks	None	Greater bone formation in all experimental groups compared to control, and greater bone formation in DBM+PRP+MSC compared to DBM+PRP	Greater bone formation in all experimental groups compared to control, and greater bone formation in DBM+PRP+MSC compared to DBM+PRP	None
Chaput et al (2007)^Citation148	Rabbit (femur)	Beaded metal implant (BMI)	BMI+PRP	BMI	5 weeks	None	None	No difference in bone growth between groups	None
Hernandez-Fernandez et al (2013)^Citation149	Sheep (femur)	None	PRP	Untreated	6 weeks	Fully blinded analysis	No difference in bone growth between groups	No difference in bone growth between groups	None
Molina-Minano et al (2009)^Citation157	Rabbit (tibia)	Autologous bone graft (ABG)	ABG+PRP PRP	ABG Untreated	8 weeks	Fully blinded analysis	No difference in bone growth between groups	No difference in bone growth between groups	None
Nather et al (2012)^Citation159	Rabbit (tibia)	Autologous bone graft Allograft	Allograft+PRP	Allograft	24 weeks	None	None	Allograft+PRP had more osteocytes than allograft alone. The greatest new bone formation, callus encasement index, and osteocyte count was seen in autograft compared to all other groups	None
Rabillard et al (2009)^Citation163	Dog (ulnar)	Calcium phosphate ceramic granules (CaP)	CaP+PRP	CaP	16 weeks	None	None	No difference in bone growth between groups	None
Sarkar et al (2006)^Citation165	Sheep (tibia)	Collagen matrix (CM)	CM+PRP	CM	12 weeks	None	No difference between groups on x-ray or CT	No difference between groups	No difference between groups
Lopez et al (2019)^Citation63	Dog (radius/ulnar and tibia/fibula)	None	PRP	Untreated	24 weeks	Fully blinded analysis	Faster rate of bone healing in the PRP group	None	None
Orth et al (2018)^Citation161	Mouse (femur)	Microcalcite (MCA)	MCP+PRP PRP	Untreated	5 weeks	None	Bone volume higher in MCRP+PRP group compared to controls	Smaller callus formation in MCP+PRP group compared to control	Polar moment of inertia (PMOI—used as surrogate for mechanical stability) higher in MCRP+PRP group compared to controls
Szponder et al (2018)^Citation173	Rabbit (tibia)	Tri-calcium phosphate (TCP)	External fixator or intramedullary nail with TCP+PRP	None	12 weeks	None	Bone formation observed in both ex-fix and IMN group	Bone formation observed in both ex-fix and IMN group	None
Canbeyli et al (2018)^Citation170	Rabbit (femur)	None	PRP	Untreated	12 weeks	X-rays	Increased union rate in PRP group	Greater cortical callus formation, woven bone percentage area, fibroblast proliferation, and mature bone formation in PRP group	None
Kim et al (2014)^Citation172	Rat (ulna)	Gelatin hydrogel	PRP+SEW2871 (macrophage recruiter) PRP	Untreated	6 weeks	None	Greater bony healing and bone density observed in the PRP+SEW and PRP groups compared to controls as assessed by micro-CT	Greater bony healing observed in the PRP+SEW and PRP groups compared to controls	None
He et al (2015)^Citation171	Rabbit (radius)	Poly (lactic-co-glycolic acid) with calcium phosphate cement (PLGA-CPC)	PLGA-CPC+PRP	PLGA-CPC	12 weeks	None	No difference in healing at 12 weeks between groups. However, micro-CT showed more bone healing in PRP group compared to control	More bone formation in PRP group compared to control	None
Shafiei-Sarvestani et al (2015)^Citation174	Rabbit (radius)	None	PRP	Untreated	8 weeks	Histology	More bone growth and union in PRP group	Greater bony healing in PRP group	Greater ultimate strength in PRP group
Weibrich et al (2004)^Citation189	Rabbit (femur)	None	PRP	Untreated	4 weeks	None	None	Higher platelet concentration in PRP group but no difference in bone healing	None
Wiltfang et al (2004)^Citation190	Mini pig (forehead)	Autologous bone graft Tricalcium-phosphate granules (Cerasorb) Bovine spongious blocks (BioOss) Bovine bone-inducing collagenous sponge (Colloss)	4 different scaffolds (listed left) with PRP (2 different concentrations)	4 scaffolds without PRP	12 weeks	None	PRP increased bone healing in the autologous bone group but not the other bone scaffold groups	PRP did not change bone healing	None
Thorwarth et al (2006)^Citation188	Pig (skull)	Autologous bone graft Deproteinized bovine bone matrix (DBBM)	2 scaffolds with PRP (2 different concentrations)	Autologous bone alone DBBM alone	26 weeks	None	No significant difference in bone mineralization	No difference in expression of bone-related gene expression	None
Bi et al (2010)^Citation139	Goat (tibia)	Tricalcium phosphate/chitosan composite (TCP)	TCP+PRP	Untreated	16 weeks	None	Improved bone healing in the TCP+PRP group	Higher rate of newly formed bone in the TCP+PRP group	TCP+PRP biomechanically equivalent to TCP alone
Kon et al (2010)^Citation184	Sheep (femur)	Hydroxyapatite-collagen nanocomposite scaffold	Hydroxyapatite-collagen nanocomposite scaffold+PRP	Untreated	24 weeks	Histology	Scaffold+PRP had worse bone regeneration than scaffold alone	Scaffold+PRP had worse bone regeneration than scaffold alone	None
Oryan et al (2012)^Citation186	Rabbit (radius)	Hydroxyapatite scaffold	Hydroxyapatite+PRP	Untreated	8 weeks	N/A	Scaffold+PRP and scaffold without PRP had equal bone formation but better than negative control	Scaffold+PRP and scaffold without PRP had equal bone formation but better than negative control	Ultimate strength greater in scaffold+PRP group compared to untreated defect control
Neves et al (2013)^Citation185	Rabbit (fibula)	None	PRP Hyperbaric oxygen + PRP	Untreated	8 weeks	None	None	Hyperbaric oxygen and PRP together or alone showed increased bone formation	None
Kasten et al (2012)^Citation183	Rabbit (radius)	Calcium-deficient hydroxyapatite (CDHA)	CDHA+PRP	CDHA alone	16 weeks	None	CDHA+PRP had greater bone formation	CDHA+PRP had greater bone formation	None
Chen et al (2013)^Citation67	Rat (femur)	None	PRP clot with low, medium, and high PRP concentrations	Untreated	8 weeks	Histology and radiology	Medium concentration PRP has increased bone healing	Medium concentration PRP has increased bone healing	Ultimate strength higher in medium concentration PRP
Gumieiro et al (2010)^Citation181	Rat (tibia)	None	PRP	Untreated	12 weeks	None	None	Increased bone formation in the PRP group	None
Filardo et al (2014)^Citation180	Sheep (metatarsal)	Biomorphic silicon carbide (BioSiC) scaffold	BioSiC+PRP	BioSiC alone	16 weeks	None	No radiographic difference in the PRP group	Increased bone formation in the PRP group	None
Velev et al (2015)^Citation179	Rabbit (tibia)	Calcium phosphate cement (CPC)	CPC+PRP	CPC alone	4 weeks	None	None	Increased bone formation in the PRP group	None
Zhong et al (2014)^Citation192	Dog (tibia)	Tricalcium phosphate (TCP)	TCP+PRP	TCP alone	12 weeks	None	Increased bone formation in the PRP group	Increased bone formation in the PRP group	Ultimate strength higher in TCP+PRP group
Qi et al (2015)^Citation141	Rat (femur)	Calcium phosphate particles (CPP)	CPP+PRP	CPP alone	4 weeks	None	Increased bone formation in the PRP group	Increased bone formation in the PRP group	None
Yilmaz et al (2014)^Citation191	Pig (tibia)	Tricalcium phosphate (TCP)	TCP+PRP	TCP alone	12 weeks	None	None	Increased bone formation in the PRP group	None
Hakimi et al (2014)^Citation182	Mini pig (tibia)	Calcium phosphate granules (CPG)	CPG+PRP+bone marrow concentrate (BMC)	CPG alone	6 weeks	None	Increased bone formation in the CPG+PRP+BMC group	Increased bone formation in the CPG+PRP+BMC group	None
Chen et al (2016)^Citation176	Rabbit (radius)	Calcium sulfate (CS)	CS+PRP PRP alone	CS alone	10 weeks	None	Increased bone formation in the CP+PRP group	Increased bone formation in the CP+PRP group	None
Bölükbaşı et al (2013)^Citation175	Sheep (tibia)	Biphasic calcium phosphate (BCP)	BCP+PRF PRF alone	Untreated	6 weeks	None	Increased bone formation in the BCP+PRF group	None	None
Schneppendahl et al (2015)^Citation187	Rabbit (tibia)	Autologous bone graft	Autograft+PRP	Autograft	6 weeks	N/A	Increased bone formation in the Autograft+PRP group	Increased bone formation in the Autograft+PRP group	None
Batista et al (2011)^Citation194	Rabbit (tibia)	Tricalcium phosphate (TCP)	TCP+PRP	TCP+bone marrow concentrate	4 weeks	None	Similar bone formation in the TCP+PRP group on x-ray but increased bone formation in the TCP+PRP group on micro-CT	Increased bone formation in the TCP+PRP group
Park et al (2016)^Citation200	Dog (femur)	None	PRF	Untreated	4 weeks	None	None	Increased bone formation in PRF group	None
Sindel et al (2017)^Citation202	Rat (skull)	None	PRF	Untreated	3 weeks	None	None	Increased bone formation in PRF group	None
Dulgeroglu et al^Citation73 (2017)^Citation195	Rat (femur)	None	PRF	Untreated	4 weeks	Histology	Increased bone formation in PRF group	Increased bone formation in PRF group	None
Akyildiz et al (2018)^Citation193	Rat (tibia)	None	PRF	Untreated	6 weeks	Radiology and histology	Reduced bone formation in PRF group	Reduced bone formation in PRF group	None
Raafat et al (2018)^Citation201	Rat (tibia)	None	PRF Simvastatin+PRF	Untreated	8 weeks	None	Increased bone formation in simvastatin+PRF group	Increased bone formation in simvastatin+PRF group	None
Lucarelli et al (2005)^Citation199	Sheep (metatarsal)	Allograft	Allograft+bone-marrow-derived stromal stem cells (BmMSCs)+PRP+collagen	Allograft alone	16 weeks	Histology	Increased bone formation in PRP group	Increased bone formation in PRP group	Higher extraction torque values in the PRP group

Table 4 Effects of PRP on Bone Healing in Clinical Studies

Author (Year)	Study Design	PRP Delivery	Bone(s) Studied	PRP Group (s)	Control Group(s)	Sorting Method	Number of Patients	Follow-Up	Outcome
Namazi et al (2016)^Citation217	Prospective randomized control trial	Intra-articular PRP injection	Radius	CRPP+PRP injection	CRPP	Non-blinded randomization	30	6m	PRP group shows decreased pain and increased function
Wei et al (2012)^Citation225	Prospective randomized control trial	Allograft bone+PRP	Calcaneus	ORIF+allograft+PRP	ORIF+allograft Autograft	Non-blinded randomization	175	72m	Better radiographic outcomes for allograft+PRP and autograft groups compared to allograft alone
Namazi et al (2016)^Citation218	Prospective randomized control trial	Intra-articular PRP injection	Scaphoid	Casting+PRP injection	Casting	Non-blinded randomization	14	6m	PRP group had decreased pain at rest and increased total function
Griffin et al (2013)^Citation210	Prospective randomized control trial	Fracture site PRP injection	Femur	CRPP+PRP injection	CRPP	Participant blinded randomization	200	12m	PRP reduced length of hospital stay, but risk of revision and clinical outcomes were equivalent
Rodriguez-Collazo et al (2015)^Citation226	Retrospective case series	Demineralized bone matrix (DBM)+PRP	Tibia/fibula	Ilizarov fixator+DBM+PRP Ilizarov fixator+DBM+concentrate bone marrow aspirate (cBMA)	Ilizarov fixator+DBM	None	20	18m	Faster radiographic healing with PRP and cBMA compared to control
Samy et al (2016)^Citation220	Prospective randomized control trial	Fracture site PRP injection	Femur	CRPP+PRP injection	CRPP	Non-blinded randomization	60	12–48m	Faster radiographic healing with PRP group, no difference in functional outcomes
Chiang et al (2007)^Citation206	Prospective case series	Bone graft and autologous platelet gel at fracture site	Femur and tibia	Internal or external fixation, ± soft tissue reconstruction	None	None	12	24–40m	Possible benefit of using PRP to treat non-unions
Lee et al (2014)^Citation213	Prospective randomized control trial	Bone marrow aspirate concentrate (BMAC)+PRP at fracture site	Tibia	External fixator (limb lengthening)	External fixator alone	Non-blinded randomization	20	24m	Significant improvement in bone formation in PRP+BMAC group
Calori et al (2008)^Citation205	Prospective randomized control trial	PRP injection at fracture site	Various	Surgical fixation + PRP	BMP-7 injection at fracture site	None	120	9–25m	Lower rate of clinical and radiographic union in PRP group compared to BMP-7 group
Liebergall et al (2013)^Citation214	Prospective randomized control trial	Demineralized bone matrix (DBM), mesenchymal stem cells (MSCs), and PRP injected into fracture site	Tibia	Surgical fixation + DBM+MSCs+PRP	Surgical fixation alone	Non-blinded randomization	24	12m	The PRP group decreased time to union
Bielecki et al (2008)^Citation204	Prospective case series	Platelet-leukocyte rich gel (PLRG) injection at fracture site	Tibia/fibula	PLRG injection to fracture site	None	None	32	9m	Possible benefit of using PRP to treat non-unions
Peerbooms et al (2012)^Citation219	Prospective randomized control trial	PRP and bone chips at fracture site	Tibia	PRP and bone chips	Bone chips alone	Non-blinded randomization	41	3m	PRP group had lower bone density
Mariconda et al (2008)^Citation216	Prospective case series (compared to historical control group)	PRP injection at fracture site	Various	PRP and external fixator	External fixator alone	None	20	9m	PRP showed equal union rates compared to controls
Dallari et al (2007)^Citation207	Prospective randomized control trial	PRP and bone chips at fracture site	Tibia	PRP and bone chips PRP+bone chips+bone marrow stromal cells	Bone chips alone	Non-blinded randomization	33	12m	Higher rates of osseointegration in both PRP groups compared to control
Sanchez et al (2009)^Citation221	Retrospective case series	PRP and bone graft at fracture site at time of surgery, then repeated PRP injections into fracture site post-operatively	Various	PRP and bone graft	None	None	15	8m	Possible benefit of using PRP to treat non-unions
Malhotra et al (2015)^Citation215	Prospective case series	PRP injection at fracture site	Various	PRP injection	None	None	94	4m	Possible benefit of using PRP to treat non-unions
Galasso et al (2008)^Citation208	Prospective case series	PRP injection at fracture site	Various	Intra-medullary nail and PRP at fracture site	None	None	22	13m	Possible benefit of using PRP to treat non-unions
Say et al (2014)^Citation222	Prospective case series	PRP injection at fracture site	Various	PRP injection at fracture site	None	None	20	12m	Possible benefit of using PRP to treat non-unions
Tarallo et al (2012)^Citation224	Retrospective case series	Bone graft+PRP	Ulna	Surgical fixation with bone graft+PRP	None	None	10	3–36m	Possible benefit of using PRP to treat non-unions
Golos et al (2014)^Citation209	Prospective case series	PRP injection at fracture site	Various	PRP injection	None	None	132	4m	Possible benefit of using PRP to treat non-unions
Bibbo et al (2005)^Citation203	Prospective case series	Autologous platelet concentrate (APC)	Various	APC+autograft APC alone	None	None	62	2m	Possible benefit of using PRP to treat high risk fractures
Kitoh et al (2007a)^Citation211	Retrospective case series	Bone marrow cells (BMCs)+PRP at distraction osteotomy site	Femur/tibia	Distraction osteogenesis BMC+PRP	Distraction osteogenesis alone	None	20	N/A	Faster union rate in BMC+PRP group
Kitoh et al (2007b)^Citation212	Retrospective case series	Bone marrow cells (BMCs)+PRP at distraction osteotomy site	Femur/tibia	Distraction osteogenesis BMC+PRP	Distraction osteogenesis alone	None	46	N/A	Faster union rate in BMC+PRP group
Sys et al (2011)^Citation223	Prospective randomized control trial	Autograft+PRP to posterior lumbar interbody fusion site	Lumbar spine	Autograft+PRP	Autograft alone	Non-blinded randomization, Radiologists were blinded	38	24m	No improvement in autograft+PRP compared to autograft alone

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