TABLE 2.
A summary of the nature and effects of biologics on graft healing after anterior cruciate ligament reconstruction (ACLR).
| Osteogenesis | Angiogenesis | Suppression of inflammation | Other mechanisms | Outcomes of graft healing (+/-/no effect) | Remarks | References | |
|---|---|---|---|---|---|---|---|
| Animal Studies | |||||||
| ADSC sheet | V | + | ADSCs stimulate bone-forming activities. ADSC sheets improved biomechanical strength, prevented bone tunnel enlargement, and promoted tendon–bone interface healing and graft remodeling in ACLR | Matsumoto et al. (2021) | |||
| BMSCs | V | + | BMSCs stimulate bone formation. It promoted graft osteointegration at the tendon–bone interface after ACLR | Hur et al. (2019) | |||
| BMP-2 Binding Peptides | V | + | The incorporation of BMP-2 binding peptides into materials used for ACLR enhanced bone formation and healing inside bone tunnels | Crispim et al. (2018) | |||
| BMSCs transfected with TGF-β gene | V | + | BMSCs are stem cells with osteogenic differentiation capacity. TGF-β is an osteogenic growth factor. BMSCs overexpressing TGF-β promoted tendon-to-bone healing after ACLR by upregulating the TGF-β/MAPK signaling pathway | Wang et al. (2017) | |||
| PRP + BMSCs | V | + | BMSC has osteogenic differentiation potential and PRP can stimulate this potential. PRP significantly stimulated osteogenic differentiation of BMSCs. The combination of PRP and BMSCs enhanced bone formation, maturation of graft-to-bone tunnel interface, and biomechanical properties of the bone–graft–bone complex | Teng et al. (2016) | |||
| SHMSP | V | + | SHMSP is an osteogenic factor. It enhanced tunnel bone formation after ACLR | Al-Bluwi et al. (2016) | |||
| AdTGF-β₁ | V | + | TGF-β is an osteogenic growth factor. Hamstring tendon transfected with AdTGF-β₁ gene promoted healing of tendon–bone interface after ACLR | Wang et al. (2015b) | |||
| hUCB-MSCs | V | + | hUCB-MSCs enhanced tendon-bone healing through broad fibrocartilage formation with higher histological scores and decreased femoral and tibial tunnel widening compared with the control group | Jang et al. (2015) | |||
| BMSC infected with BMP-2 gene | V | + | BMSCs have osteogenic differentiation potential. BMP-2 can induce osteogenic and chondrogenic differentiation of pluripotent stem cells and bone progenitor cells. The transplantation of BMSCs genetically modified with BMP-2 enhanced the osseointegration of the tendon graft within the host bone | Dong et al. (2012) | |||
| Rat kidney cell line transduced with pCMV-BMP-2 gene | V | + | BMP-2 is an osteogenic growth factor. It enhanced osteogenesis at the tendon graft-to-bone tunnel interface after ACLR. | Wang et al. (2010) | |||
| PRP/DPB complex | V | + | The mixture of PRP/DPB enhanced chondrogenesis, Sharpey’s fiber formation and graft incorporation into the bone tunnel at 60% PRP | Zhao and Zhai, (2010) | |||
| TGF-β1 | V | + | TGF-β1 is an osteogenic growth factor. It enhanced tunnel bone formation | Yamazaki et al. (2005) | |||
| TGF-β+EGF | V | + | TGF-ß increases both collagen and noncollagenous protein synthesis. EGF stimulates fibroblast proliferation in vitro. Application of TGF-β and EGF improved the structural properties of the bone–graft–bone complex after ACLR | Yasuda et al. (2004) | |||
| Bone-derived extract (Bone Protein, Sulzer Biologics, Wheat Ridge, Colorado) | V | + | Bone-derived extract (Bone Protein, Sulzer Biologics, Wheat Ridge, Colorado) is effective in augmenting bone ingrowth. It improved healing of a tendon graft in a bone tunnel in an intra-articular ligament-reconstruction model | Anderson et al. (2001) | |||
| ACL-derived CD34+ cell sheet transduced with VEGF gene or sFLT-1 | V | + | ACL-derived CD34+ cells expressing moderate levels of VEGF improved tendon graft maturation and biomechanical strength; however, CD34+ overexpressing VEGF promoting excessive angiogenesis impeded graft healing and mechanical strength. The transplantation ACL-derived CD34+ cell sheet secreting sFLT1, a soluble VEGF inhibitor decreased angiogenesis, delayed graft maturation, and decreased biomechanical strength of the bone–graft–bone complex | Takayama et al. (2015) | |||
| VEGF | V | _ | VEGF is an angiogenic growth factor. Excessive angiogenesis reduced integrity and stiffness as well as increased laxity of graft | Yoshikawa et al. (2006) | |||
| PDGF-BB | V | + | PDGF has a positive effect on revascularization. The local long-term application of PDGF using a biodegradable drug delivery tool biomechanically and histologically improved free tendon graft remodeling after ACLR | Weiler et al. (2004) | |||
| Synovium-derived cells pre-treated with TGF-β1 or TGF-β1 | V | + | The transplantation of synovium-derived cells cultured in TGF-β1 or TGF-β1 inhibited the deterioration of the intra-articular part of tendon graft after ACLR | Kondo et al. (2011) | |||
| PRP | V | V | + | PRP contains PDGF, VEGF, and TGF-β. It increased the bioactivity of the tendon–bone interface and resulted in histological improvement at the tendon–bone junction | Zhang et al. (2019) | ||
| hBMSC-CM | V | V | + | hBMSC-CM contains a variety of growth factors, including TGF-β, VEGF, and IGF. It accelerated graft osteo-integration and mid-substance ligamentization after ACLR | Sun et al. (2019) | ||
| Muscle-Secreted Factors | V | V | + | Muscle-secreted factors influences revascularization and tendon–bone closure. Using a rat model of ACLR showed that conditioned media derived from human muscle tissue accelerated femoral tunnel closure, a key step for autograft integration | Ghebes et al. (2018) | ||
| α-FGF | V | V | + | α-FGF is a mitogenic factor of osteoblasts and chondrocytes as well as an angiogenic factor. It induced fibrocartilage formation at the tendon–bone interface after ACLR | Lu et al. (2018) | ||
| ACL-derived CD34+ cells transduced with BMP-2 | V | V | + | ACL-derived CD34+ cells transduced with BMP-2 can stimulate angiogenesis and osteogenesis at the graft-bone interface. ACL-derived CD34+ cells transduced with BMP-2 accelerated graft–bone integration after ACLR | Kawakami et al. (2017) | ||
| BMSCs and VEGF | V | V | + | BMSCs have osteogenic potential and VEGF promotes angiogenesis. All parameters using MRI, collagen type III expression, and biomechanical analysis of pullout strength of the graft showed that application of intra tunnel BM-MSCs and VEGF enhanced tendon-to-bone healing after ACLR | Setiawati et al. (2017) | ||
| BMSCs genetically modified with bFGF/BMP-2 | V | V | + | bFGF can promote angiogenesis and BMP-2 has osteogenic potential. The addition of BMP-2 or bFGF by gene transfer resulted in better cellularity, new bone formation, and higher mechanical property, which contributed to the healing process after ACLR | Chen et al. (2016) | ||
| ADRC | V | V | + | ADRCs secrete significantly larger amounts of growth factors, such as VEGF, hepatocyte growth factor than BMSCs. Local administration of ADRCs promoted the early healing process at the tendon–bone junction, both histologically and mechanically, after ACLR | Kosaka et al. (2016) | ||
| Fibrin clot | V | V | + | Transplantation of fibrin clot improved graft healing as shown by histology and MRI | Hensler et al. (2015) | ||
| TDSC sheet | V | V | + | TDSCs are stem cells with osteogenic differentiation capacity. TDSC sheet expressed bFGF, TGF-β1 and BMP-2 which have angiogenic and osteogenic effects. The transplantation of TDSC sheet promoted bone formation, enhanced graft osteointegration and graft mid-substance integrity, as well as improved biomechanical properties of the bone–graft–bone complex | Lui et al. (2014c) | ||
| TGF-β1 plasmid in liposomes | V | V | + | TGF-β1 increases angiogenesis and induces fibroblast, monocyte, and macrophage migration to sites of injury, promoting ligament healing. Injection of TGF-β1 plasmid in liposomes into bone tunnel improved biomechanical characteristics of the bone–graft–bone complex | Qin et al. (2013) | ||
| ACL-derived CD34+ cell sheet | V | V | + | CD34+ cells are endothelial cells that secrete angiogenic and osteogenic factors. The transplantation of ACL-derived CD34+ cell sheet enhanced healing of the bone–tendon junction and the grafted tendon by promoting proprioceptive recovery, graft maturation, and biomechanical strength. The outcomes were better after transplantation of the cell sheet compared with cell injection | Mifune et al. (2013) | ||
| ACL-derived CD34+ cell | V | V | + | CD34+ cells are endothelial cells which secrete angiogenic and osteogenic factors. Intracapsular injection of CD34+ cells post-ACLR increased biomechanical strength of the bone–graft–bone complex via enhancement of angiogenesis and osteogenesis at graft-bone interface at early stage after ACLR | Mifune et al. (2012) | ||
| Platelet | V | V | + | Platelet contains PDGF, VEGF, and TGF-β. The addition of blood platelets resulted in significant reduction in anterior-posterior knee laxity after ACLR | Spindler et al. (2009) | ||
| G-CSF | V | V | + | G-CSF contributes to angiogenesis and osteogenesis. A local application of G-CSF-incorporated gelatin significantly accelerated bone-tendon interface strength via enhanced angiogenesis and osteogenesis | Sasaki et al. (2008) | ||
| Human Studies | |||||||
| hUCB-MSCs | V | No effect | The transplantation of allogeneic hUCB-MSCs did not show any clinical advantage such as the prevention of tunnel enlargement, knee laxity, and clinical outcomes | Moon et al. (2021) | |||
| PRP | V | + | PRP contained bone growth factors. The administration of PRP decreased the rate of second ACL injury compared with the literature | Berdis et al. (2019) | |||
| PRP | V | No effect | The administration of PRP did not prevent tunnel enlargement after ACLR | Sözkesen et al. (2018) | |||
| PRP | V | + | PRP contained bone growth factors. The application of PRP prevented femoral tunnel widening in ACLR | Starantzis et al. (2014) | |||
| PRP | V | No effect | The application of PRP did not reduce tunnel enlargement after ACLR | Vadalà et al. (2013) | |||
| PRP | V | + | PRP contained bone growth factors. It enhanced the formation of focal areas of sclerotic cortical bone with subsequent fusion into a thick tibial tunnel wall after ACLR | Rupreht et al. (2013b) | |||
| PRP | V | No effect | The administration of PRP to bone tunnels reduced tunnel widening, but the difference was not statistically significant | Mirzatolooei et al. (2013) | |||
| PRP | V | No effect | PRP contained growth factors with osteogenic activities. There was no significant improvement in tendon graft incorporation to the bone tunnel after ACLR | Silva and Sampaio, (2009) | |||
| PRPG | V | + | PRPG contains PDGF. It decreased edema and increased vascularity at the tibial tunnel after ACLR | Rupreht et al. (2013a) | |||
| PG | V | + | PG contained PDGF. It enhanced vascularization at the tibial tunnel interface and intra-articular part of the graft | Vogrin et al. (2010) | |||
| PRF | V | V | No effect | The administration of PRF did not significantly improve graft failure and graft ligamentization up to 12 months post-ACLR | Zeman et al. (2018) | ||
| PRP | V | V | No effect | The administration of PRP did not accelerate graft interface healing and graft ligamentization after ACLR | Komzák et al. (2015) | ||
| PRFM | V | V | + | PRFM has a substantial amount of growth factors (such as TGF-β1, PDGF, VEGF). PRFM-augmented patients showed a statistically significant higher patient-reported knee function | Del Torto et al. (2015) | ||
| PRP | V | V | + | The administration of PRP accelerated graft mid-substance remodeling after ACLR. | Seijas et al. (2013) | ||
| PRP | V | V | + | PRP contained PDGF, TGF-β1, and VEGF which were osteogenic and angiogenic. The administration of PRP enhanced graft mid-substance remodeling compared with the untreated grafts | Sánchez et al. (2010) | ||
| ACS | V | V | + | ACS contains endogenous anti-inflammatory cytokines including IL-1Ra and growth factors (IGF-1, PDGF, and TGF-b1) in the liquid blood phase. Intra-articular administration of ACS decreased bone tunnel widening and reduced the level of IL-1β in the synovial fluid after ACLR | Darabos et al. (2011b) | ||
Note. N.B.
ACS, autologous conditioned serum; ADSC, adipose derived stem cell; ADRC, adipose-derived regenerative cell; AdTGF-β1, adenovirus-mediated transforming growth factor β1; BMP-2, bone morphogenetic protein-2; BMSCs, bone marrow mesenchymal stem cells; hBMSC-CM, hBMSC–conditioned medium; pCMV, plasmid cytomegalo virus; DPB, deproteinized bone; EGF, epidermal growth factor; α-FGF, acidic fibroblast growth factor; bFGF, basic fibroblast growth factor; G-CSF, granulocyte colony-stimulating factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor-1; PDGF-BB, platelet-derived growth factor–BB; PG, platelet gel; PRPG, platelet-rich plasma gel; PRFM, platelet-rich fibrin matrix; PRF, platelet-rich fibrin; PRP, platelet-rich plasma; SHMSP, Sadat–Habdan mesenchymal stimulating peptide; TGF-β, transforming growth factor–β; TDSC, tendon-derived stem cell; hUCB-MSCs, umbilical cord blood-derived mesenchymal stem cells; VEGF, vascular endothelial growth factor.