Cellular Conversations: Signal-Driven Regeneration - Advances in Orthopedic Healing, Biochemical and Mechanical Stimulation

In our Cellular Conversations blog post series, we described the biochemical, mechanical and electrical signals that bone cells use to facilitate growth and repair. This post delves into how scientists and surgeons are leveraging the knowledge of biochemical and mechanical signals to develop advanced bone repair therapies.

PART 3: Biochemical Signals – Enhancing Repair with Growth Factors and Cytokines

Of the many growth factors explored for bone repair, bone morphogenetic proteins have received the most attention in terms of research, FDA-approvals, and clinical use (Table 1).

Table 1: Clinical Use of Biochemical Signals for Bone Repair

Growth Factor	Role	Application	Products
Bone Morphogenetic Proteins (BMPs)1-8	Differentiation of mesenchymal stem cells (MSC) into osteoblasts Induction of osteogenesis Regulation of chondrogenesis	Spinal fusions, tibial fractures, cranioplasty	BMP-2 (rhBMP-2) BMP-7 (OP-1) FDA-approved 2002
Platelet-Derived Growth Factor (PDGF)6,8	Stimulates cell proliferation, angiogenesis, and recruitment of MSC to the repair site	Periodontal bone repair, surgical fusion of the ankle and hindfoot, distal radius fractures.	GEM 21S FDA-approved 2005
Vascular Endothelial Growth Factor (VEGF)6	Improves repair site vascularization	Ossification and vascularization in critical-sized mandibular bone and calvaria defects.	Not approved stand-alone
Fibroblast Growth Factor-2 (FGF-2)6,9	Stimulates angiogenesis Proliferation of osteogenic cells	Regeneration of mandible cortical bone	Approved in some countries
Insulin-like Growth Factor-1 (IGF-1)10,11	Enhances osteoblast proliferation and differentiation Matrix synthesis	Clinical studies to improve bone healing with growth hormone	Not approved stand-alone
Parathyroid Hormone (PTH)12	Stimulates osteoblast activity and bone remodeling	Osteoporosis treatment, off-label use for bone healing	Teriparatide (PTH 1-34)

Therapeutic use of growth factors presents challenges, including high production costs and the need for controlled application to avoid complications like ectopic bone formation, inflammation, or increased cancer risks. Novel carriers and biologics such as polymers, composites, hydrogels, ceramics, and others are under study to provide controlled and sustained release methods. 2,3,5,7

Mechanical Signals – Promoting Faster Bone Repair (Table 2)

The most common clinical use of mechanical signaling in bone repair is through physical therapy, although results are difficult to quantify. Physical therapy plays a crucial role in the mechanical stimulation of bone growth through weight-bearing exercises, which apply load stress to the bone, promoting remodeling and growth. Range of motion exercises enhance blood flow and nutrient delivery to the fracture site, while muscle strengthening exercises increase support and stability, effectively distributing the mechanical load. These combined methods promote bone mass and mineralization; however, standardizing these therapies can be challenging due to factors like fracture location and treatment variables.

Table 2: Clinical Use of Mechanical Signals for Bone Repair

Mechanical Signal	Application	Advantages	Limitations
Distraction Osteogenesis13	Oral, orthopedic, craniofacial, and plastic surgery	No bone tissue transplant needed	Long consolidation period, pain, infection, nonunion
Physical Therapy14	Enhances fracture healing Prevents bone loss	Promotes bone mass and remodeling	Fatigue, lack of motivation, long duration required
Low-Intensity Pulsed Ultrasound (LIPUS)15	Stimulates bone formation and healing at fracture sites	Noninvasive, no side effects, low cost	No improvement in weight-bearing capacity, pain reduction
External Fixators16	Stabilize fractures Aid weight-bearing to promote healing	Provides stability, corrects alignment	Long duration for frame removal, pin-track infections

Other techniques such as distraction osteogenesis and low-intensity pulsed ultrasound (LIPUS) are also used clinically to improve bone repair through mechanical signaling. Distraction osteogenesis is a surgical technique involving an incision in the bone to place a distractor, which gradually separates the bone at a controlled rate, typically a few millimeters per day. As the bone is stretched, new tissue forms within the gap, allowing for bone lengthening or repositioning. This technique is used in craniofacial surgery to correct jaw deformities and in trauma-related orthopedic surgeries but is associated with a high risk of complications.17

Despite FDA approval for nonunion fractures, low-intensity pulsed ultrasound (LIPUS) products have not consistently reduced recurrent fractures.14-16 External fixators aid in controlled movement and load distribution across the fracture site, essential for bone healing. Pins secure the external frame of clamps and rods to the bone, but careful management is required to mitigate the risk of infection.  

At Molecular Matrix, Inc., we leverage our expertise in signal-driven regeneration to develop novel bone graft substitutes, facilitating effective treatment for fractures and bone injuries. To learn more about Molecular Matrix, Inc. click here.

References

1. Singh H, Moss IL. Biologics in Spinal Fusion. In: Biologics in Orthopaedic Surgery [Internet]. Elsevier; 2019 [cited 2024 Jun 20]. p. 165–74. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780323551403000151

2. Senarath-Yapa K, McArdle A, Renda A, Longaker M, Quarto N. Adipose-Derived Stem Cells: A Review of Signaling Networks Governing Cell Fate and Regenerative Potential in the Context of Craniofacial and Long Bone Skeletal Repair. Int J Mol Sci. 2014 May 26;15(6):9314–30.

3. Mariani E, Pulsatelli L, Facchini A. Signaling Pathways in Cartilage Repair. Int J Mol Sci. 2014 May 15;15(5):8667–98.

4. Halloran D, Durbano HW, Nohe A. Bone Morphogenetic Protein-2 in Development and Bone Homeostasis. J Dev Biol. 2020 Sep 13;8(3):19.

5. Mendenhall SK, Priddy BH, Mobasser JP, Potts EA. Safety and efficacy of low-dose rhBMP-2 use for anterior cervical fusion. Neurosurg Focus. 2021 Jun;50(6):E2.

6. Oliveira ÉR, Nie L, Podstawczyk D, Allahbakhsh A, Ratnayake J, Brasil DL, et al. Advances in Growth Factor Delivery for Bone Tissue Engineering. Int J Mol Sci. 2021 Jan 18;22(2):903.

7. Tateiwa D, Kaito T. Advances in bone regeneration with growth factors for spinal fusion: A literature review. North Am Spine Soc J NASSJ. 2023 Mar;13:100193.

8. Gillman CE, Jayasuriya AC. FDA-approved bone grafts and bone graft substitute devices in bone regeneration. Mater Sci Eng C. 2021 Nov;130:112466.

9. Krticka M, Planka L, Vojtova L, Nekuda V, Stastny P, Sedlacek R, et al. Lumbar Interbody Fusion Conducted on a Porcine Model with a Bioresorbable Ceramic/Biopolymer Hybrid Implant Enriched with Hyperstable Fibroblast Growth Factor 2. Biomedicines. 2021 Jun 25;9(7):733.

10. Giustina A, Mazziotti G, Canalis E. Growth Hormone, Insulin-Like Growth Factors, and the Skeleton. Endocr Rev. 2008 Aug 1;29(5):535–59.

11. Locatelli V, Bianchi VE. Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis. Int J Endocrinol. 2014;1–25.

12. Silva BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol. 2015 Jun;22:41–50.

13. Yang S, Wang N, Ma Y, Guo S, Guo S, Sun H. Immunomodulatory effects and mechanisms of distraction osteogenesis. Int J Oral Sci. 2022 Dec;14(1):4.

14. Księżopolska‑Orłowska K. Changes in bone mechanical strength in response to physical therapy. Pol Arch Intern Med. 2010 Sep 1;120(9):368–73.

15. Palanisamy P, Alam M, Li S, Chow SKH, Zheng Y. Low‐Intensity Pulsed Ultrasound Stimulation for Bone Fractures Healing: A Review. J Ultrasound Med. 2022 Mar;41(3):547–63.

16. Simpson AHRW, Robiati L, Jalal MMK, Tsang STJ. Non-union: Indications for external fixation. Injury. 2019 Jun;50:S73–8.

17. Liu, Q., Liu, Z., Guo, H. et al. A comparative study of bone union and nonunion during distraction osteogenesis. BMC Musculoskelet Disord 23, 1053 (2022). https://doi.org/10.1186/s12891-022-06034-w