Cureus, 09/05/2026
Introduction
Orthopedic biologics (orthobiologics) are biological agents that support tissue repair and regeneration, derived from autologous or allogeneic sources, including PRP, BMAC, mesenchymal stem cells (MSCs), growth factors (BMPs), biological scaffolds, extracellular matrix, and gene technology. They act on the tissue microenvironment, promoting natural healing processes and functional recovery, rather than relying solely on mechanical fixation and symptom relief.
In trauma, orthobiologics enhance the fracture healing process through four stages: inflammation, soft callus, hard callus, and remodeling. Injury reduces perfusion, progenitor cells, and cytokine signaling, leading to delayed bone healing. Orthobiologics support healing by providing scaffolding for cell guidance, growth factors that promote osteogenesis and angiogenesis, and progenitor cells that regulate inflammation and promote endochondral bone formation. They are particularly useful in complex fractures (open fractures, delayed union, non-union, and cartilage/soft tissue injuries), where fixation alone is insufficient, helping to improve callus formation and repair.
Despite their strong potential in musculoskeletal treatment, clinical evidence remains limited. Many therapies have been commercialized without robust efficacy data, while concerns persist regarding safety, manufacturing consistency, and long-term outcomes. These knowledge gaps still require further research and clarification.
Review
Materials and Methods
A total of 987 initial records were identified; after removing duplicates (n=432), titles and abstracts were screened for eligibility. Forty-seven articles were selected for full-text review.
Inclusion criteria comprised human studies (clinical trials, cohort studies, systematic reviews, or meta-analyses) on the application of orthobiologics in fracture healing, non-union, or trauma-related soft tissue repair, with full-text availability. Ultimately, 17 studies were included in the analysis.
Results
Types of Orthobiologics and Mechanisms of Action
- Blood-derived therapy (PRP):
PRP is an autologous platelet-rich preparation containing growth factors (PDGF, TGF-β, VEGF) that stimulate chemotaxis, angiogenesis, and cell proliferation at the injury site. PRP promotes the early inflammatory phase, enhances osteoblast differentiation, and supports soft callus formation. It also activates extracellular matrix (ECM) regeneration, increasing synthesis of components such as collagen, fibronectin, and proteoglycans, thereby providing a provisional scaffold for tissue repair.
- Cell-based therapy (MSCs/BMAC):
MSCs are multipotent progenitor cells capable of differentiating into bone, cartilage, and fibrous tissues, and of secreting cytokines, chemokines, and growth factors that modulate immune responses, reduce inflammation, and promote tissue regeneration. Their primary effect is mediated through paracrine signaling, stimulating endogenous cells and angiogenesis.
BMAC is an autologous concentrate derived from bone marrow, enriched in MSCs, platelets, and growth factors (PDGF, TGF-β, VEGF, IGF), which enhances cell proliferation, angiogenesis, and ECM synthesis, while also modulating inflammation and recruiting endogenous progenitor cells.
- Growth factors & recombinant proteins:
BMPs (BMP-2, BMP-7) stimulate osteoblast differentiation via SMAD signaling, promoting bone formation. VEGF enhances endothelial cell proliferation and angiogenesis, ensuring oxygen and nutrient supply to tissues. TGF-β (particularly TGF-β1 and TGF-β2) is involved in bone remodeling and tissue repair; TGF-β1 regulates osteogenesis and wound healing but may induce fibrosis when overexpressed, whereas TGF-β2 supports chondrogenesis and ECM deposition. Exogenous use requires controlled delivery systems to avoid adverse effects.
Table 1. Summary of Growth Factor-Based and Tissue-Derived Orthobiologics in Trauma
| Orthobiologic Agent | Source | Key Functional Components / Growth Factors | Primary Target Tissue(s) | Trauma / Regenerative Application |
| BMP‑2 BMP‑7 | Recombinant proteins (rhBMPs) | BMP‑2, BMP‑7 (osteogenic growth factors) | Bone & osteoprogenitors | Nonunion, open fractures, bone reconstruction |
| VEGF | Platelets, MSCs, injury milieu | VEGF‑A | Endothelial cells & angiogenic zones | Critical in early fracture healing and large defect repair |
| TGF‑β | Platelets, bone matrix | TGF‑β1, TGF‑β2, TGF‑β3 | Cartilage, bone, connective tissues | Supportive in fracture callus and cartilage repair |
| Fibroblast Growth Factors (FGFs) | Platelets, mesenchymal cells | FGF‑2, FGF‑18 (various isoforms) | Mesenchymal progenitors, osteoblasts, chondrocytes | Early healing phases of bone/soft tissue trauma |
- Biomaterials & scaffolds:
These include hydrogels, collagen matrices, and 3D-printed structures that provide structural support and controlled delivery of biological factors. They facilitate cell adhesion, recruit progenitor cells, and enhance the retention and activity of cells/growth factors at the injury site, thereby improving tissue regeneration. Injectable hydrogels containing BMPs, MSCs, or growth factors can degrade in synchrony with the healing process, maintaining a local therapeutic concentration and reducing the risk of ectopic bone formation.
Current Evidence: Applications of Orthobiologics in Trauma Healing
- Acute fracture healing (closed and open fractures):
Orthobiologics aim to enhance inflammation, recruit progenitor cells, and promote angiogenesis to support callus formation. PRP shows inconsistent results: it may shorten healing time and improve intermediate callus formation in some groups (particularly tibial shaft fractures), but does not consistently improve union rates. BMPs (especially BMP-2) have the strongest evidence in open fractures, helping to reduce time to union. BMAC and MSCs provide support in open fractures, improving union rates and reducing infection/delayed healing through progenitor cell supplementation and improved perfusion.
- Delayed union and non-union:
These conditions represent disruptions of the normal bone healing process and are key indications for orthobiologics. PRP (alone or combined with bone grafting) shows increased union rates (~85.8% vs ~60.8% in controls) and pain reduction. Meta-analyses indicate that PRP and BMPs outperform standard care in both healing time and union rate. MSC therapy achieves union rates of approximately 91%, shortens healing time, and is associated with low complication rates.
- Tendon & ligament injury:
PRP is widely studied due to its ease of preparation and high growth factor content. Preclinical studies show that PRP stimulates tenocyte proliferation, collagen synthesis, and angiogenesis. However, clinical outcomes are variable; some studies report improvements in pain and function, while others show no significant difference compared with controls.
- Complex trauma & segmental bone loss:
In large defects, mechanical support and biological regeneration must be combined. Orthobiologics are often used with scaffolds: PRP within scaffolds enhances MSC viability, proliferation, migration, and differentiation; combination with osteoconductive materials (bioactive glass, hydroxyapatite, chitosan) improves bone regeneration and defect closure. PRP- and MSC-loaded scaffolds demonstrate significant cell growth and tissue regeneration after 12 weeks, highlighting their potential in complex clinical scenarios.
Table 2. Clinical Evidence of Orthobiologics in Trauma Sub‑Domains
| Orthobiologic | Sub‑types | Evidence Level | Clinical Outcomes |
| PRP | Leukocyte‑rich PRP Leukocyte‑poor PRP | RCTs, Cohort Studies | Mixed results in acute fractures and non‑unions due to protocol variability. Some studies show improvement in radiographic healing time |
| RCT | PRP reduces healing time and improves mid-stage callus formation in tibial shaft fractures | ||
| Comprehensive review | PRP improves bone mineral density and shortens fracture healing duration in tibial fractures | ||
| PRP + Bone Graft | PRP + autologous graft PRP + synthetic graft | Meta-analysis, Cohort Studies | Accelerated healing in delayed union fractures; enhanced bone consolidation when combined with autologous bone graft. |
| MSCs | BMAC Adiposederived MSCs | Systematic review and meta-analysis | High union rates; reduced delayed union |
| Composite Scaffolds + Orthobiologics | PRP‑laden Gelatin Microspheres PRP + Bioactive Glass | Preclinical Data | Improved MSC survival, proliferation, and osteogenic differentiation in large bone defect models; higher osteogenic differentiation and tissue recovery |
| PRP + Osteoconductive Carriers | PRP + Hydroxyapatite, Chitosan | Preclinical Data | Enhanced defect closure and bone mineralization in segmental bone defects; increased tissue recovery over 12 weeks in scaffold‑MSCs studies. |
Limitations and Challenges
Orthobiologics in trauma face several important limitations that hinder standardization and optimal clinical application, despite their significant potential. The major challenge is the lack of uniformity in preparation protocols, dosing, terminology, and outcome reporting. For example, PRP shows substantial variation between platelet-rich, leukocyte-rich, and centrifugation-based preparation methods, leading to variability in growth factor release of up to approximately 40% across studies. Similarly, BMAC and MSCs also lack standardization due to differences in harvesting sites, processing methods, and cell viability, making comparisons across trials difficult.
High-quality clinical evidence has not kept pace with the widespread use of orthobiologics, partly due to the presence of unregulated providers offering cell-based and injectable biologic therapies without sufficient evidence, resulting in inconsistent outcomes and potential safety concerns. In addition, the regulatory framework is complex: under FDA/HCT/P regulations, products may be classified as “minimally manipulated” or “more than minimally manipulated,” and this classification directly affects approval pathways, clinical labeling, and safety monitoring.
Future Directions and Regenerative Strategies
The field of orthobiologics is moving toward precision and personalized medicine, in which patients’ biological characteristics such as inflammatory markers, aging-related biomarkers, and genetic factors are used to select appropriate regenerative therapies, rather than applying a uniform approach for all cases. The integration of molecular biomarkers, high-resolution imaging, and artificial intelligence may help determine optimal dosing, select combination therapies, and improve the prediction of clinical responses in musculoskeletal regeneration.
A notable research direction is cell-free therapy, particularly exosomes and extracellular vesicles (EVs). These are natural signaling molecules involved in intercellular communication, carrying various bioactive factors capable of modulating inflammation, promoting angiogenesis, and stimulating osteogenic and chondrogenic responses. Preclinical studies indicate that EVs can suppress inflammation, enhance bone and cartilage regeneration, regulate extracellular matrix metabolism, and modulate tissue regenerative signaling pathways, while also potentially offering a safer profile compared to whole-cell therapies.
Conclusions
Orthobiologics (PRP, BMAC/MSCs, BMPs) are transforming the trauma treatment paradigm toward biological regeneration, particularly in cases of delayed and non-union fractures, where they increase union rates and shorten healing time. They also play a supportive role in acute fractures and soft tissue defects, complementing biological healing when conventional treatments may be insufficient.
Although not widely used in acute fractures, orthobiologics may help reduce the need for revision surgery and improve recovery in complex cases. The future of this field is closely linked to protocol standardization, personalized medicine, and the development of advanced regenerative platforms such as exosomes and bioengineered scaffolds.
References
Al-Rumaih M, Al-Hoshan W, Al-Shehri M, et al. (2026) Orthobiologics in Trauma: Current Trends, Future Directions, and Regenerative Strategies. Cureus 18(5): e108535.
Source: Cureus
Link: https://assets.cureus.com/uploads/review_article/pdf/492763/20260509-372712-cuh4vr.pdf
