Maxillofacial Reconstruction With Three Dimensional Resin Bone Substitutes as an Alternative to Transition Group of Metals: A Structured Review

In recent years, novel technologies and techniques have allowed today the production of controlled architecture materials. Although autogenous bone graft substitutes remain the gold standard, enormous defects require supplementary alloplastic substitutes for reconstruction. Polymers have lately been explored for the same purpose and their biological performance has been under research since the last decade. The aim of this review is to analyse maxillofacial reconstruction with three-dimensional resin bone substitutes. A Problem Intervention Comparison Outcomes (PICO) analysis was done and a search was carried out in the Cochrane Database, PubMed, Google Scholar etc databases and a hand search was done to collect the related literature. All articles for maxillofacial reconstruction with three-dimensional resin bone substitutes were scrutinised. The manuscripts published from 1990 till May 2021, were included in this review. A total of 106 articles were obtained from a PICO-based keyword search, and 91 manuscripts were retrieved after excluding the duplicates. Out of these 57 manuscripts were excluded on the basis of title and abstract. From the remaining 34 studies, 17 were excluded after reading the full text based on the inclusion and exclusion criteria. During data extraction, four studies were removed and finally, 13 studies were included in this research. From this scoping review, we could conclude that polymethylmethacrylate and polylactic acid formulations are very promising resin bone substitutes for 3-dimensional reconstruction of maxillofacial defects. However, rigorous long-term clinical trials are needed to validate this conclusion.


Introduction And Background
Bone substitutes are popularly used in neurosurgery, orthopedics, and dental surgical procedures [1].Their use has escalated with the latest development of injectable graft materials [2].In craniofacial defects, transition metals are an age-old used biomaterial with long-term survival [3].Recently, the most promising alloplastic materials commonly used include Poly Lactic acid Glycolic Acid (PLGA) and Poly Methyl Meth Acrylate (PMMA) [4].PGLA-based scaffolds have suitable bone regenerative capacity and exhibit excellent prospects for bone repair [5,6].Porous PMMA is a biocompatible material produced from PMMA powder and MMA liquid in which carboxymethylcellulose gel in the aqueous form is dispersed to generate pores that enable ingrowth resulting in improved acceptance of the graft [7][8][9].
In recent years, unique and innovative technologies have enabled the production of controlled architecture grafts.Various studies have been done time and again to experiment on the coating of implants [10,11], bone substitutes, etc.Studies show promising results for alloplastic substitutes as successful bone substitutes for enhanced regenerative properties.PLGA bio-polymers have been instrumental in applications in tissue engineering [12][13][14][15].Many challenges faced in this research include potential risks like immunogenicity, toxicity, and prone to infections.Despite being biocompatible, the practical application of pure PLGA for bone regeneration in clinical scenarios is impeded by various drawbacks, including reduced osseoconductivity and unsatisfactory mechanical properties for load-bearing areas.
Today, numerous bone graft materials are commercially procurable.Nevertheless, there is no clarity in the consensus regarding the use of suitable bone graft material in specific practical configurations like maxillofacial prostheses [16,17].Furthermore, the outlooks of alloplastic bone substitutes are also based on the trends among countries and their current market status.About 36 alloplastic graft materials, since 1980, have been approved by the Ministry of Health & Welfare database in Korea.Since 1996, the United States Food and Drug Administration has recorded 87 alloplastic materials approved for use as grafts in the United States.According to the Pharmaceuticals and Medical Devices Agency records, since 2004 about 10 materials have been permitted for use in Japan.The approved alloplastic bone substitutes include hydroxyapatite, biphasic calcium phosphate, and β-tricalcium phosphate.The development of new bone alloplastic grafts is ongoing in the biomaterial research sector.In the future, alloplastic bone grafts could be the first choice instead of autogenous bone, provided they pass the necessary safety and quality standardization.They may provide enhanced osteoconductive and osseoinductive effects in combination with better handling and optimal resorption rate.The objective of this review is to evaluate the existing evidence on maxillofacial reconstruction with three-dimensional (3D) resin bone substitutes.

Review Structured question
Is there a significant difference between polymethyl methacrylate and polylactic acid when used as a bone substitute in discontinuity defects?Problem Intervention Comparison Outcomes (PICO) analysis: Pdiscontinuity defect, I -polymethyl methacrylate, C -polylactic acid, O -bone gain.

Literature sources used
For the analysis of studies retrieved for this scoping review, the search methodology used suitable keywords in the PICO format.They describe population, intervention, comparison, and outcome.To obtain articles electronically, within each group, OR boolean was used and the searches of individual groups were coupled using AND boolean.The electronic databases included were: PubMed, Google Scholar, Cochrane Database of Systematic Reviews, Embase, Scopus, Web of Science, and Science Direct.Comparison: polylactic acid substitute, polylactic acid copolymer, polylactic acid substitutes, polylactic acid copolymers, poly(lactic-co-glycolic acid), polyethylene, porous polyethylene, polymer bone substitutes, polycaprolactone.

Search terms
Outcome: bone gain, bone turnover, bone formation, bone regeneration, bone fill, bone augmented, newly formed bone, bone growth.

Article eligibility criteria
The inclusion criteria included articles containing discontinuity type of defect, articles with polymer-based bone substitutes, randomized control trials, cohort studies, prospective or retrospective studies, and articles including composite graft materials with the intervention and/or comparison.The exclusion criteria were any other defect apart from discontinuity defect, any other alloplastic bone substitutes, case series, reviews, case reports, and articles containing hip arthroplasty.

Results
A total of 106 articles were obtained from keyword search (based on PICO), and 91 manuscripts were retrieved after excluding the duplicates.Out of these 57 manuscripts were excluded on the basis of title and abstract.From the remaining 34 studies, 17 were excluded after reading the full text based on the inclusion and exclusion criteria [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34].During data extraction, four studies were removed and finally, 13 studies were included in this research (Figure 1).The excluded studies and their reason for exclusion are described and tabulated (Table 1).The statistical significance, mean values of outcome measures and conclusion of each retrieved article were extracted (Table 3).

Discussion
The current review included 13 articles after exclusions and the core data was tabulated and assessed.The analysis describes the use of resin bone graft substitutes in various defects.Out of the 13 studies, only two studies involved human subjects which were retrospective in nature (Table 2).The majority of the included articles are in vitro studies or studies on animal models, which highlights the novelty of the intervention group studied [35][36][37][38][39][40][41][42][43][44][45][46][47].
PMMA as a bone graft has been sporadically used as graft material due to its desirable injection properties and sufficient mechanical properties.Research in this aspect has established favorable bioactivity, high cell viability, potential guided tissue regeneration membrane, and bone ingrowth into the prostheses [38,42].
However, certain shortcomings such as questionable efficiency in the biological environment, increased temperature, and toxicity due to monomers do exist.Various studies tried to alter PMMA bone grafts by surface coating them with polydopamine-strontium calcium polyphosphate (D/SCPP), titanium dioxide, calcium phosphate, antibiotics, etc. to overcome its clinical disadvantages.
Another important problem regarding the PMMA-based graft is the interface between bone and cement which tends to be a weak zone.This essentially is the reason for the development of PMMA coatings, doped PMMA, and composite graft solutions [39,40].Time and again in vitro models and animal studies have shown promising evidence that PMMA can be used in defect coverage, especially craniofacial defects with a set of challenges [48,49].
The limitations of this study comprise the in-vitro and animal model-based studies included with level V evidence (according to the Centre for Evidence-Based Medicine, Oxford, England) and the lack of randomized control trials in humans with the intervention or comparison groups.Therefore, the inference must be perceived cautiously.The future scope of this research could include multicentre trials in humans with more randomization and stricter protocols for consideration.

Conclusions
Based on the analysis of this review, we could conclude that polymethylmethacrylate is a very potential bone substitute for 3-dimensional reconstruction of maxillofacial defects.However long-term clinical trials are required for rigorous validation.With the alloplastic bone graft materials being an advanced grafting solution option for various defects, they may be a likely substitute in the near future.

FIGURE 1 :
FIGURE 1: PRISMA flowchart depicting the total number of articles obtained, the non-duplicate articles screened, the excluded articles (by title/abstract, full text screen , data extraction ) and finally the number of articles retrieved PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses