Update on synthetic biomaterials combined with fibrin derivatives for regenerative medicine: Applications in bone defect treatment: Systematic review

Table 1 Studies published since 2013 on synthetic biomaterials combined with fibrin derivatives in bone

Ref.	Objective	Study type	Biomaterial	Methods	Outcome measures
Studies with HA as the main component
Reis et al[33], 2022	To evaluate the ceramic biomaterial with heterologous FB and PBM	In vivo (animal model: Male Wistar rats)	HA/tricalcium phosphate (BP) ceramic (B); FB; PBM with gallium-aluminum-arsenide	Parietal osteotomies (5 mm) were performed on 56 rats. Four groups were established: Biomaterial only, biomaterial + FB, biomaterial + PBM, and biomaterial + FB + PBM	PBM with low-level laser therapy positively influenced the repair of bone defects filled with FB associated with BCP
Meimandi-Parizi et al[39], 2018	To compare the effects of combinations of gel, PR-FG, and nHA with the use of nHA alone	In vivo (animal model: Mature male Wistar albino rats)	Gel-nHA (4.29 wt% aqueous solution of gel) and PR-FG derived from rat PRP	Bilateral 5 mm osteotomies were performed on the radial diaphysis of 30 rats. Six groups were established: Empty defect (–C), autologous graft (+C), and defects filled with nHA, gel + nHA, PR-FG + nHA, and gel + PR-FG + nHA	All groups showed bone formation and remodeling. PR-FG + nHA achieved superior mechanical strength and healing compared to +C. Gel + PR-FG + nHA regenerated moderately
Kustermans and Mommaerts[25], 2017	To describe the modified Turkish Delight technique for dorsal augmentation using HA combined with Surgicel®	In vivo (women)	Hydroxyapatite-calcium carbonate matrix (ProOsteon® 200R), monolayer of oxidized cellulose (Surgicel®), and FS (Tissel®)	Four women (17–32 years old) with congenital defects were treated using hydroxyapatite-calcium carbonate particles wrapped in oxidized cellulose and fixed with 1–2 cm³ FS, inserted endonasally	Stable, satisfactory outcomes with gradual mineralization were observed. At 4 months, HA granules remained visible; at 1 year, the material formed a homogeneous mass. There was no degradation at 2 years
Chen et al[26], 2013	To evaluate a biomaterial combining a biphasic calcium phosphate (HA/β-TCP) osteoconductive scaffold with allogeneic platelet FG	In vivo (humans)	Platelet gel, cryoprecipitate, and endogenous thrombin were prepared from PRP, cryoprecipitate, and fresh frozen plasma (FFP). HA/β–TCP (60%-40%), allogeneic platelet FG	Ten patients (20–52 years old) with orbital floor fractures (1–2 cm²) were treated with PR-FG, prepared by mixing FFP, HA/β-TCP, and activated PRP	The material was easy to handle and mold, with no leakage. All patients showed successful defect restoration. Long-term bone formation likely replaced the biomaterial
Jang et al[38], 2014	To investigate the non-autologous Transplantation of hMSCs for regenerating osteochondral defects using a scaffold composed of PR-FG and HA	In vivo (animal model: White rabbits)	hMSCs, PR-FG and HA	Osteochondral defects (6 × 8 mm) were created in the femoropatellar groove of 28 rabbits. Five groups were established: Untreated, HA, HA + PR-FG, HA + PR-FG + undifferentiated, and HA + PR-FG + differentiated hMSCs	After 8 weeks, the HA + PR-FG + differentiated hMSCs group showed superior healing, better cartilage integration, and significantly higher histological scores
Filardo et al[27], 2014	To evaluate C-HA scaffolds in cadaveric knees under CPM, with and without loading, and assess the effect of FG addition	Ex vivo human cadaver	The osteochondral scaffold was a three-layered C-HA structure: (1) A cartilaginous layer made of type I collagen; and (2) An intermediate layer made of type I collagen (60%) + HA (40%); and a subchondral bone layer made of a mineralized blend of type I collagen (30%) and HA (70%). FG (Tisseel®)	Osteochondral defects were created in cadaveric knees. C-HA scaffolds were implanted using press-fit or FG. Two FG-fixed knees underwent loading and continuous passive motion	FG fixation improved outcomes (Drobnic: 4.3 vs 2.9; Bekkers: 5.0 vs 3.3). Knee loading did not compromise scaffold integrity
Martinčič et al[28], 2019	To evaluate patients with ACI grafts for graft-related or unrelated SAEs	In vivo (humans)	Classical periosteum-ACI, fibrin-collagen patch (Tachocomb®), collagen membrane (Chondrogide®), alginate-agarose hydrogel (Gel4Cell®), and three-layered C-HA biomimetic scaffold (Maioregen®)	Prospective 18-year study with 151 patients receiving ACI via various carriers: Periosteum, fibrin-collagen patch, FG, alginate-agarose hydrogel, or Maioregen®. Grafts were implanted through arthrotomy	Ten-year follow-up showed 86% graft survival. SAEs occurred in about 21%, but none led to definitive failure. Female patients had a 2.8 × higher risk of failure, particularly after cartilage surgery
Mazzone et al[31], 2018	To describe the outcomes of using a synthetic bone substitute combined with PRF	In vivo (humans)	A biphasic resorbable biomaterial composed of 50% HA and 50% PLGA (ReOss®) and an autologous PRF	Fifteen patients with cysts, trauma, or atrophy in the jaws, mandible, or zygomatic bone received grafts covered with a PRF membrane	Wound dehiscence occurred in four cases but healed without affecting regeneration. At 3–6 months, all patients showed satisfactory healing and mature bone formation
Taufik et al[32], 2022	To examine the potential use of bovine HA xenograft and PRF in the treatment of bone defects	In vivo (humans)	Bovine HA and PRF	Three patients (2 women and 1 man) with delayed or non-union fractures (humerus, femur, tibia) were treated with internal fixation, bovine HA, and PRF	All showed good to excellent bone restoration, full joint function, and no pain. HA + PRF accelerated healing
Studies with HA + β-TCP as main components
Cassaro et al[37], 2019	To evaluate BCP and FB, combined or not with MSCs	In vivo (animal model: Male Wistar rats)	BCP composed of 60% HA and 40% β-TCP (Graftys® BCP, Graftys Sarls, France), FB, and MSCs	Femoral osteotomy (5 × 2 mm) in 80 rats. Five groups were established: Empty defect, BCP, FB + BCP, FB + MSCs, and FB + BCP + MSCs	FB was biocompatible and served as a scaffold. FB + MSCs showed greater bone matrix formation, even without prior osteogenic differentiation
Della Coletta et al[36], 2021	To evaluate the effects of PBM on GBR in rat Calvarial defects filled with BCP combined with FB	In vivo (animal model: Male Wistar rats)	BCP composed of 70% HA and 30% β-TCP (GenPhos XP®, Baumer SA), FBP, and resorbable bovine cortical bone membrane (GenDerm®, Baumer SA) (ROG)	Parietal osteotomies were performed in 5 mm in 30 rats. Groups included BMG (BCP), BFMG (BCP + FB), and BFMLG (BCP + FB + PBM); all defects were covered with a membrane	All groups showed bone formation, with BFMLG presenting the greatest increase. PBM enhanced and accelerated regeneration when combined with BCP and FB
Nair et al[43], 2020	To investigate the use of β-TCP associated with hMSCs combined with FG	In vitro	β-TCP, HA nanopowder, and hMSCs from the iliac bone	Twenty β-TCP scaffolds. Group A was seeded with osteogenic hMSCs + FG, and Group B (control) included β-TCP + FG only	Group A showed superior bone regeneration, increased angiogenesis, improved cell infiltration, and preserved mechanical strength
Guastaldi et al[35], 2022	To evaluate a biomaterial made of ACP, octacalcium phosphate, and HA	In vitro and in vivo (animal model: Male white rabbits)	ECP, FS (Center for the Study of Venoms and Venomous Animals), (DBB, Bio-Oss®), and β-TCP (Cerasorb®)	Parietal osteotomies (10 mm) were performed in 45 rabbits. Groups included: ECP, ECP + FS, coagulum, autograft, DBB, and β-TCP. All defects were covered with a collagen membrane	DBB and β-TCP combined with ECP showed increased BV/TV over time. ECP particles decreased in size, and giant cells were frequent. ECP had lower RUNX-2 but higher ALP levels than the other groups
Süloğlu et al[44], 2019	To compare the synthetic biphasic ceramic Ceraform® (CR) coated with FG or FN, seeded with osteogenically induced ADMCs	In vitro	CR, composed of 65% HA and 35% β-TCP; ADMCs; FG (Tisseel®); and bovine plasma-derived FN	ADMCs were cultured in OIM and seeded on CR scaffolds coated with FG (CR-FG) or FN. FG allowed cell embedding via clot formation	Both coatings induced osteogenic markers. CR-FG showed better cell survival, remodeling, and protein expression, including type 1 collagen and BMP-2
Nacopoulos et al[23], 2014	To compare the healing properties of PRF and its combination with a graft composed of HA and β-TCP	In vivo (animal model: New Zealand white rabbits)	Autologous PRF and HA/β-TCP (60% HA and 40% β-TCP)	Bone defects (4 × 8 mm) were created in femoral condyles of 15 rabbits. Each animal received PRF in one limb and PRF + synthetic graft in the other	The PRF + G group showed a statistically significant higher mean bone healing density, as well as greater cortical and subcortical bone formation
Studies with Fibrin as the main component
Goto et al[34], 2016	To evaluate the combined use of an Atelocollagen sheet and FG for sellar reconstruction	In vivo (animal model: Female Wistar rats)	FG, atelocollagen sheet, PGA sheet, and autologous fat tissue	A bilateral 5 mm osteotomy was performed on the parietal bones of eight rats. Experimental groups: FG (Control group), atelocollagen + FG (CLG Group), PGA + FG (PGA Group), and autologous fat tissue + FG (Fat Group)	At 5 weeks, atelocollagen and PGA remained, while FG and fat were absorbed by week 2. Inflammation was lower around atelocollagen than around PGA
Mordenfeld et al[29], 2013	To evaluate graft healing and volumetric changes after lateral augmentation with two different materials: DPBB and AB	In vivo (humans)	DPBB (Bio-Oss®), monocortical AB block, and FG (Tisseel®)	Split-mouth RCT with 13 patients (6 men and 7 women). Jaws were augmented using 60: 40 or 90: 10 DPBB: AB grafts, both with FG and collagen membranes	The 60 40 group showed greater ridge gain and less graft resorption than the 90 10 group. New bone formation was similar, but soft tissue predominated near the periosteum in both groups
Bojan et al[30], 2022	To evaluate the feasibility of bonding freshly harvested human trabecular bone with OsStic® compared to FG	Ex vivo	Phosphoserine-modified cement (OsStic®) and FG (Tisseel®)	Thirteen femoral heads were obtained from arthroplasty patients (8 men and 5 women). Bone cores were reattached using a bone adhesive (n = 10) or FG (control group)	The FG group achieved a peak force of 5.4 ± 1.6 N. The bone adhesive bonded effectively to wet, fatty, osteoporotic bone
Witek et al[41], 2020	To evaluate the effect of the leukocyte- and Platelet-rich fibrin (L-PRF)/PLGA composite graft on bone regeneration	In vivo (animal model: Female sheep)	PLGA: 85/15 ratio of dl-lactide/glycolide; porous scaffolds; and L-PRF	Submandibular defects (0.40 cm³) were created bilaterally in six sheep. Groups included no L-PRF (control) and PLGA/L-PRF blocks (experimental)	Both groups showed bone formation, with significantly higher bone occupancy in the L-PRF group (38.3% vs 28%)
Studies with β-TCP as the main component
Tee et al[40], 2016	To evaluate cell- and growth factor-based reconstruction of mandibular defects and compare scaffold materials and sealing methods	In vivo (animal model: Female domestic pigs)	β-TCP, BM-MSCs and PLGA	Mandibular defects (5 cm³) were created in six pigs. The groups were: A (β-TCP), B (β-TCP + BM-MSCs), and C (β-TCP + BM-MSCs + BMP-2/VEGF microspheres). Groups B and C were sealed with FS or PLGA membranes	Groups B and C showed greater regeneration, density, and remodeling than Group A. β-TCP degradation was delayed by membrane sealing and was not macrophage- or osteoclast-dependent
Cakir et al[42], 2019	To evaluate the effect of the MPM, composed of a synthetic graft and platelet concentrates, on bone regeneration	In vivo (animal model: Male sheep)	MPM, β-TCP, and PRF	Five tibial bone defects were created in six sheep. The groups included: Empty control, MPM, β-TCP, PRF + β-TCP, and autograft	At 3 and 6 weeks, autograft had the most frequent bone formation. MPM showed better healing and bone formation than β-TCP. All groups showed reduced graft remnants over time

ADMC: Adipose-derived mesenchymal cells (s); CR: Alternative synthetic biphasic ceramic Ceraform^®; ACP: Amorphous calcium phosphate; AB: Autogenous bone; ACI: Autologous chondrocyte implantation; β-TCP: Beta-tricalcium phosphate; BCP: Biphasic bioceramic; BM-MSCs: Bone marrow-derived mesenchymal stem cells; BMP-2: Bone morphogenetic protein-2; BV/TV: Bone volume as a percentage of total volume; C-HA: Collagen-hydroxyapatite; Col-I: Collagen type I; CPM: Continuous passive motion; DBB: Deproteinized bovine bone; DPBB: Deproteinized bovine bone particles; ECP: Experimental calcium phosphate; FN: Fibronectin; FB: Fibrin biopolymer; FG: Fibrin glue; FS: Fibrin sealant; FFP: Fresh frozen plasma; GBR: Guided bone regeneration; HMSCs: Human mesenchymal stem cells; HA: Hydroxyapatite; L-PRF: Leukocyte- and platelet-rich fibrin; MPM: Mineralized plasma matrix; Nha: nanohydroxyapatite; PBM: Photobiomodulation; PRF: Platelet-rich fibrin; PR-FG: Platelet-rich fibrin glue; PRP: Platelet-rich plasma; PLGA: Poly (D,L-lactide-co-glycolide); PGA: Polyglycolic acid; SAE: Serious adverse events.