Endogenous jaw bone regeneration: past, present, and future

Abstract

Jaw bone defects impair oral function and facial aesthetics, reducing patients’ quality of life. While significant progress has been achieved in systemic skeletal repair, jaw bone regeneration remains challenging due to its distinct biological and anatomical features compared with long bones. This article systematically traces the evolution of jaw bone regeneration from conventional guided bone regeneration to bioactive scaffold–based tissue engineering. Mechanism-driven strategies tailored for jaw bone regeneration under compromised bone microenvironment are also discussed, with a specific focus on diabetes. A clear understanding of the evolution of strategies for jaw bone regeneration and the challenges posed by impaired bone microenvironment will foster innovation in this field and improve clinical outcomes.

Introduction

Jaw bone defects caused by trauma, infection, tumor resection, and congenital deformities severely impair jaw function and facial aesthetics, thereby reducing patients’ quality of life. Unlike long bones, jawbones arise from distinct developmental origins and therefore exhibit unique biological and anatomical features, making regeneration in the maxillofacial region particularly challenging [1]. However, most current regenerative strategies are derived from long bone research and cannot be directly translated to jaw bone repair.

Bone tissue engineering has emerged as a promising alternative to conventional grafting approaches in jaw bone regeneration [2]. Its efficacy relies on three core elements: bioactive scaffolds, seed cells, and growth factors and is profoundly influenced by the bone microenvironment, a dynamic niche composed of cells, extracellular matrix, and signaling molecules, which governs bone homeostasis and repair. Although strategies such as guided bone regeneration (GBR) and bone morphogenetic protein 2 (BMP-2) delivery have achieved clinical success, their regenerative outcomes are often compromised in aging, metabolic disorders, and inflammation, where the altered microenvironment suppresses osteogenesis [3]. Therefore, a clear understanding of the current challenges of endogenous jaw bone regeneration is essential for the development of more effective therapies.

This perspective summarizes the evolution of jaw bone regeneration from conventional GBR to BMP-2-based regenerative strategies, and highlights future directions for bone repair under compromised microenvironment. (Figure 1).

Figure 1:

Schematic illustration of the progression of jaw bone regeneration strategies from traditional guided bone regeneration to BMP-2 induced bone regeneration, with emphasis on the current challenges of achieving effective bone regeneration under impaired microenvironmental conditions such as diabetes. BMP-2, bone morphogenetic protein 2.

Guided bone regeneration for jaw bone repair

Jaw bone reconstruction has evolved from autologous grafting and distraction osteogenesis to GBR. Autografts remain the gold standard owing to their osteogenic potential, but their application is limited by donor site morbidity and restricted graft supply. Distraction osteogenesis exploits the intrinsic regenerative capacity of the mandible by inducing new bone formation through controlled mechanical tension after osteotomy. Despite its biological advantages, its broader use is restricted by prolonged treatment duration, soft tissue–bone imbalance, and the risk of nerve injury.

GBR was then developed to address these limitations. By combining barrier membranes with bone substitutes such as Bio-Oss^® or cancellous freeze-dried bone allograft (FDBA), GBR prevents soft tissue invasion while maintaining a three-dimensional space for cell migration, vascular ingrowth, and new bone formation. It is widely used in partially and fully edentulous patients and is guided by the PASS principles: primary closure, angiogenesis, space maintenance, and stability of the wound and implant. Nevertheless, membrane collapse, wound dehiscence, and inconsistent healing continue to compromise clinical outcomes, stimulating the development of more advanced biomaterial-based strategies.

BMP-2-induced jaw bone regeneration

Among bioactive molecules, FDA-approved recombinant human BMP-2 (rhBMP-2) is one of the most effective molecules for oral and periodontal bone regeneration. Unlike growth factors that primarily promote proliferation or migration, BMP-2 recruits endogenous stem cells and directs their differentiation toward the osteoblastic lineage, thereby reducing dependence on exogenous cell transplantation.

The integration of BMP-2 with structurally optimized scaffolds has improved alveolar bone regeneration and expanded the regenerative potential of GBR-based therapies. Liu et al. developed a BMP-2-loaded channel-integrated tenting screw that functioned as a bioactive alternative to conventional membranes. This system enhances the recruitment and osteogenic differentiation of soft tissue–derived Prrx1⁺ stem cells, which maintains a stable regenerative microenvironment, thereby facilitating coordinated bone formation within both soft and hard tissues at the defect site [4]. To address wound closure difficulties caused by soft tissue tension, Gao et al. designed a minimally invasive self-expanding scaffold loaded with BMP-2. Following expansion, the scaffold maintains a stable regenerative space while BMP-2 promotes osteogenesis [5].

Despite these advances, the clinical use of rhBMP-2 remains constrained by its narrow therapeutic window. The FDA-approved concentration for human use is 1.5 mg/mL, which has also shown efficacy in extraction socket augmentation [6]. However, BMP-2 is dosage-dependent, with low doses being ineffective and high doses inducing postoperative inflammation and ectopic bone formation. Therefore, the central challenge is not simply increasing BMP-2 loading, but improving its therapeutic efficiency so that lower and safer doses can achieve comparable outcomes. One promising strategy is the incorporation of functional metal ions that potentiate BMP-2 activity. Among these, magnesium ions (Mg²⁺) are known to participate in osteogenic signaling pathways and can synergize with BMP-2 to enhance bone formation, thereby reducing the required BMP-2 dosage [7]. Nevertheless, broader clinical translation of rhBMP-2 is still hampered by burst release from conventional carriers, high manufacturing cost, and concerns regarding off-target osteogenesis. Future studies should therefore focus on optimizing the delivery system and advancing protein purification procedures to maximize efficacy, safety, and clinical translatability.

Jaw bone regeneration under impaired bone microenvironment

Jaw bone repair remains challenging under pathological conditions such as diabetes mellitus. Diabetes increases the risk and severity of periodontitis, accelerates alveolar bone loss, and impairs healing after tooth loss. Persistent hyperglycemia disrupts the local microenvironment, compromises cellular functions and consequently hinders bone repair. As a result, strategies based solely on scaffolds and osteogenic molecules often fail to achieve predictable outcomes under diabetic conditions. These limitations highlight the need to elucidate the biological mechanisms governing impaired bone healing and to develop more targeted interventions.

Bone is a highly innervated tissue, and growing evidence indicates that neural regulation is indispensable for bone regeneration [8]. The nervous system influences bone metabolism both directly, by modulating osteoblast and osteoclast activity through nerve-derived signals, and indirectly, through nerve-resident cells such as Schwann cells, which exert paracrine effects. Disruption of this neuro–skeletal interaction, as occurs in diabetic neuropathy, can impair osteogenesis. In diabetic long-bone repair, strategies that promote innervation – such as functional mitochondrial transfer or reversal of hyperglycemia-induced Schwann cell senescence – have significantly improved healing. Similar mechanisms appear to operate in alveolar bone. In type 2 diabetes, reduced nociceptive innervation has been associated with impaired alveolar bone regeneration, whereas activation of these nerves promotes repair [9]. Likewise, diabetes-associated periodontitis is characterized by a loss of calcitonin gene-related peptide (CGRP)⁺ nerves, which contributes to alveolar bone loss. Sustained delivery of CGRP using an injectable hydrogel enhances type H vessel formation and supports Osterix⁺ osteoprogenitors, thereby alleviating periodontitis-induced bone loss [10]. Beyond local regulation, the nervous system also influences bone regeneration through systemic metabolism, neuroendocrine pathways and neuro-immune crosstalk. These observations identify the nervous system as a critical determinant of bone regeneration in compromised conditions and a promising therapeutic target.

In addition to diabetes, osteoporosis, rheumatoid arthritis, and aging-related cellular senescence also generate hostile microenvironments that impair jaw bone healing. Given the increasing prevalence of metabolic disease and the rapid aging of the global population, regenerative strategies capable of overcoming compromised systemic conditions are urgently needed. Although major progress has been made in skeletal repair, effective approaches for jaw bone regeneration under pathological microenvironments remain to be investigated.

Conclusions

Jaw bone defects impose severe functional and psychological burdens, highlighting the need for more effective regenerative therapies. Although GBR and BMP-2-based approaches have demonstrated clinical value, their efficacy is often limited by pathological microenvironments. A deeper mechanistic understanding of dysregulated osteogenesis is therefore essential for the design of targeted regenerative strategies.

Looking forward, the convergence of biomaterials with advanced technologies, including microelectronics and artificial intelligence, may enable intelligent regenerative platforms capable of continuously monitoring mechanical stress, inflammation, temperature, and other local cues during healing. Such systems could support real-time, personalized intervention and improve regenerative precision. Despite the strong promise of these emerging approaches, robust clinical evidence is still required to bridge the gap between experimental innovation and clinical practice. Overall, multidisciplinary advancements hold immense potential to revolutionize jaw bone reconstruction, ushering in a new era of regenerative medicine.