Comparative Analysis of Trends in Biomaterials for Bone Regeneration: A Bibliometric Perspective

Abstract

Natural bone regeneration often falls short for complex or large defects, making costly bone grafting procedures a necessary intervention. Tissue engineering provides promising alternatives, and biomaterial selection is strongly crucial for its success. This study provides a bibliometric analysis from 2000 to 2024, comparing research trends on 35 biomaterials or regenerative strategies in bone regeneration, as well as active countries, clinical trials, and both animal and bone defect models. Our findings reveal declining trends for some calcium phosphate materials (i.e., biphasic calcium phosphate and tricalcium phosphate), stable trends for hydroxyapatite, and increasing research engagement for bioactive glasses and several natural polymers (i.e., silk fibroin, chitosan, alginate, gelatin, hyaluronic acid, and cellulose). However, collagen showed a declining research interest. From synthetic polymers, polycaprolactone is gaining research interest, while polylactic-co-glycolic acid and poly(methyl methacrylate) are declining. Newer advancements (i.e., exosomes, polydopamine coating, and graphene-based materials), gene therapy strategies, and peptides showed growth. Conversely, calcium sulfate, bone morphogenetic proteins, and platelet-rich plasma are declining. These comparative insights inform future research and biomaterial selection in bone regeneration.

Impact Statement

This is the first bibliometric comparison of various biomaterials and regenerative strategies for bone regeneration, analyzing global publication trends from 2000 to 2024. The study reveals which biomaterials are gaining research momentum and which are losing focus, offering a strategic lens for future investigation and clinical translation.

Keywords

osteogenesis bone substitutes fracture healing scaffolds biomaterials trend analysis

Introduction

Bone tissue has a remarkable capacity for self-regeneration and repair, largely due to its vascularized structure, dynamic remodeling capabilities, and natural turnover.^1,2 While this natural healing is generally sufficient for minor injuries, in complex conditions like nonunions, malunions, tumor-related bone defects, avascular necrosis, severe osteomyelitis, and large bone defects, the body’s natural healing ability falls short.³ In such cases, external interventions become critical, as spontaneous repair tends to be slow and insufficient to restore full recovery, resulting in considerable physical and social burdens for patients.^4,5 Autologous bone grafting is the gold standard for the treatment of bone defects.⁶ Bone grafting is the second most frequently transplanted tissue after blood transfusions.^3,7 Each year, around 2 million bone grafting procedures are conducted worldwide.³ The global annual expenditure for treating bone defects is estimated to be $45 billion.^8,9 The Bone Health and Osteoporosis Foundation estimates that the overall cost of managing osteoporotic fractures and nonunion fractures in Europe could hit $55 billion by 2030.^10,11 Bone grafts have several limitations, including donor site morbidity and limited availability in autologous grafts, and immunological or infectious risks in allogeneic grafts.^12,13

The field of tissue engineering is rapidly advancing as a critical approach to treating bone defects, generating rising interest among researchers.¹⁴ Various regeneration strategies are being developed to facilitate better bone repair and address the limitations of natural healing.¹⁰ The selection of biomaterials plays a crucial role in determining the success of these approaches, with key characteristics such as biocompatibility, biodegradability, mechanical strength, and the ability to support cell adhesion and growth being essential for effective bone regeneration.¹⁰

In recent years, regenerative medicine for bone regeneration has gained increasing attention. However, to the best of our knowledge, a bibliometric analysis summarizing and comparing different materials in this field has not yet been conducted. There remains a gap in quantitative analysis, particularly in understanding research trends. Through comparative data analysis, researchers can better understand ongoing trends and make informed choices in future experimental design and biomaterial selection.¹⁴ The aim of this study is to conduct a comprehensive analysis comparing the research trends of various biomaterials and regenerative medicine strategies employed in bone regeneration. The analysis also includes an assessment of the most active countries contributing to each biomaterial, the number of clinical trials associated with each material, and the distribution of both bone defect and animal models used for each approach.

Method

A systematic search was conducted in the Scopus database, limited to original research articles published between 2000 and 2024. Only original articles were included; reviews, conference papers, book chapters, and other nonoriginal formats were excluded. No language restrictions were applied to capture global research trends. For this analysis, the yearly count of material-specific articles was adjusted by dividing it by the total bone regeneration articles published in the respective year. We referred to the resulting ratio as the “interest rate.” A similar normalization was applied to country-level publication outputs. It should be noted that this metric serves as a measure of relative research attention within the scholarly literature, not of public or clinical interest.

Yearly i nterest r ate = \frac{Material - s pecific p ublications in y ear “ y ”}{Total b one r egeneration p ublications in y ear “ y ”}

Country - based i nterest r ate = \frac{Material - s pecific p ublications in c ountry “ c ”}{Total b one r egeneration p ublications in c ountry “ c ”}

For each material, a search syntax was developed and combined with the bone regeneration syntax and improved through several rounds of refinement. Synonyms and related terms were identified using MeSH terms and articles, and we randomly reviewed abstracts from preliminary search results to evaluate their relevance, repeating the process until unrelated results were largely eliminated. The search syntax used for the overall bone regeneration studies is provided in the Supplementary Material, and a representative example of the search syntax for hydroxyapatite (HA) has also been provided. Upon establishing the appropriate search syntax, we conducted searches within titles, abstracts, and keywords. Limiting the scope to these fields was intended to enhance specificity and reduce unrelated records, as in most bibliometric studies.^15,16

Global interest rate assessment

To measure the global research interest in bone regeneration, we included only those countries that had published more than 500 scientific articles on the topic between 2000 and 2024. This cutoff was determined through a pilot assessment of multiple potential thresholds (e.g., 200, 400, 500, 1,000), and the 500-publication level was found to best ensure a more accurate and representative estimation of global interest, while minimizing the risk of inflated interest rates due to limited publication output in certain countries. Additionally, a higher threshold would have excluded a substantial number of countries, whereas the 500-publication cutoff appeared to offer a balanced approach. Based on this criterion, a total of 53 countries met the inclusion requirements.

Assessment of animal models and clinical trials

To evaluate the frequency of animal model usage for each biomaterial, a targeted analysis was conducted using specific search syntaxes for individual animal types (detailed in the Supplementary Material). Additionally, the proportion of large animal models relative to the total number of animal studies was calculated as an indicator of the translational maturity and developmental stage of research for each material.

Furthermore, data from ClinicalTrials.gov were analyzed to determine the number of registered clinical trials involving each material, irrespective of the trial status (e.g., ongoing, completed, withdrawn). Finally, the most commonly targeted bone types for each material were identified to better understand their primary applications in bone regeneration research.

Materials with fewer than 300 published articles were excluded from further analysis. This threshold was set to ensure reliable results, as lower counts would not support trustworthy insights, while a higher cutoff would have excluded a considerable portion of relevant materials.

Data analysis and visualization were conducted using Microsoft Excel and PowerPoint.

Results

Bone regeneration articles

The Scopus database (2000–2024) yielded a total of 405,930 articles. After excluding nonoriginal articles, a total of 326,768 publications were identified (Fig. 1). The field has experienced a 347.5% growth in publications from 2000 to the end of 2024, with an average annual growth rate of 6.57%. The most rapid expansion occurred between 2018 and 2020, with an average yearly increase of 13% in publications. Additionally, 3,599 clinical trials were recorded in ClinicalTrials.gov on the topic.

FIG. 1.

Search strategy and selection process.

Global scientific production for bone regeneration

The United States leads in research on bone regeneration with a total of 77,559 articles published from 2000 to 2024. Following the United States is China with 60,754 articles, Germany’s contribution is 23,542. Japan ranks next with 20,949 publications, closely followed by the United Kingdom with 20,035 and Italy with 15,911. India has 14,761 articles, South Korea 12,053, France 11,524, and Turkey 10,156 articles (Fig. 2).

FIG. 2.

Trends in bone regeneration research. (A) Annual scientific production of bone regeneration articles. (B) Global scientific production in bone regeneration.

Hydroxyapatite and calcium-deficient hydroxyapatite

From 2000 to 2024, research on HA increased significantly, reaching its highest engagement in 2016 and 2017. Its popularity has since plateaued. Indonesia shows the greatest focus on HA studies, followed by Malaysia, Iran, Portugal, and Romania. Research primarily examines long bones, especially the femur and tibia, along with the maxillofacial region. Studies using animal models frequently involve rats among small models, while dogs are the most used large models, followed by goats and sheep (Fig. 3). Additionally, 70 clinical trials have explored HA for bone regeneration.

FIG. 3.

Trends in hydroxyapatite research. (A) Annual scientific production of hydroxyapatite-related articles. (B) Relative interest in hydroxyapatite research, expressed as the ratio of hydroxyapatite articles to total bone regeneration studies per year. (C) Global interest rate in hydroxyapatite. (D) Pie chart demonstrating the distribution of bone types in hydroxyapatite studies. (E) Pie chart illustrating the distribution of animal models for hydroxyapatite research.

Dicalcium phosphate

Dicalcium phosphate (DCP) encompasses both dicalcium phosphate anhydrous (DCPA, CaHPO₄) and dicalcium phosphate dihydrate (DCPD, CaHPO₄·H₂O). From 2000 to 2024, research on DCP saw steady growth, though recent data indicate a sharp decline in research engagement. Morocco showed the highest focus on DCP studies, followed by Russia, Iraq, Iran, and Indonesia. Research primarily concentrated on long bones, particularly the femur and tibia, followed by calvarial and maxillofacial regions. Among animal studies, rabbits were the most used small models followed by rats, and dogs were the most used large animal models followed by pigs (Fig. 4). One clinical trial has explored the use of DCP in bone regeneration.

FIG. 4.

Trends in DCP research. (A) Annual scientific production of dicalcium phosphate (DCP)-related articles. (B) Relative interest in DCP research, expressed as the ratio of DCP articles to total bone regeneration studies per year. (C) Global interest rate in DCP. (D) Distribution of bone types in DCP studies. (E) Distribution of animal models for DCP research.

Tricalcium phosphate

Interest in tricalcium phosphate (TCP) research rose steadily from 2000; 2014–2018 appears to have been a peak period for TCP research, and it has declined in interest ever since. Singapore, Iraq, Ukraine, Portugal, and Hungary demonstrated the highest focus on TCP studies. Investigations predominantly targeted long bones, followed closely by the maxillofacial regions. Among animal models, rats were most frequently used in small animal studies, while dogs were the leading choice among large animals, followed by goats and sheep (Fig. 5). Additionally, 60 clinical trials have examined the application of TCP for bone regeneration. Also, it is interesting to know that β-TCP was used in articles around 7.4 times more than α-TCP.

FIG. 5.

Trends in tricalcium phosphate (TCP) research. (A) Annual scientific production of TCP-related articles. (B) Relative interest in TCP research, expressed as the ratio of TCP articles to total bone regeneration studies per year. (C) Global interest rate in TCP. (D) Pie chart demonstrating the distribution of bone types in TCP studies. (E) Pie chart illustrating the distribution of animal models for TCP research.

Octacalcium phosphate

Between 2000 and 2013, interest in octacalcium phosphate (OCP) research experienced considerable fluctuations, and from 2013 to 2022, OCP was rapidly growing and reached its peak in 2022 with 39 articles but has since been in decline. However, given the low publication numbers, such fluctuations are natural and may not necessarily reflect future directions. Interestingly, Japan had the highest number of articles related to OCP. When considering the proportion of OCP studies relative to a country’s total bone regeneration research, Russia ranked first, followed by Japan, Croatia, Mexico, and Iran. It seems like Russia and Japan both had a high number of articles and a high interest rate in OCP. The distribution of bone types and animal models is illustrated in Figure 6.

FIG. 6.

Trends in octacalcium phosphate (OCP) research. (A) Annual scientific production of OCP-related articles. (B) Relative interest in OCP research, expressed as the ratio of OCP articles to total bone regeneration studies per year. (C) Global interest rate in OCP. (D) Pie chart demonstrating the distribution of bone types in OCP studies. (E) Pie chart illustrating the distribution of animal models for OCP research.

Biphasic calcium phosphate

Interest in biphasic calcium phosphate (BCP) research peaked in 2015 and 2016, exceeding 1% of total articles, marking the golden years for BCP research, though the interest rate has gradually declined since. South Korea, Iraq, Portugal, Ukraine, and Malaysia showed the highest focus on BCP studies relative to their total bone research. Investigations primarily targeted the maxillofacial region and long bones. In animal model studies, rats and rabbits were the most frequently used among small animals, and dogs were the most frequently used large animal model followed by goats and sheep (Fig. 7). Additionally, 33 clinical trials have explored BCP for bone regeneration.

FIG. 7.

Trends in biphasic calcium phosphate (BCP) research. (A) Annual scientific production of BCP-related articles. (B) Relative interest in BCP research, expressed as the ratio of BCP articles to total bone regeneration studies per year. (C) Global interest rate in BCP. (D) Pie chart demonstrating the distribution of bone types in BCP studies. (E) Pie chart illustrating the distribution of animal models for BCP research.

Calcium phosphate-based materials

Calcium phosphate (CaP)-based materials (including HA, TCP, OCP, etc.) represented one of the most widely researched classes in bone regeneration. The highest interest rate was observed in 2016, marking the most active period for this research area. From that point, interest declined modestly until 2019 and then stabilized through 2024, suggesting this field has achieved a degree of maturity. Indonesia, Portugal, Malaysia, Iran, and Romania showed the greatest proportional emphasis on CaP-related studies. The studies mainly focused on long bones followed by the maxillofacial regions. In terms of animal models, rats were most frequently used, followed by rabbits among small animals. Among large animals, dogs were the most common, followed by goats and sheep (Fig. 8). Furthermore, 161 clinical trials listed on ClinicalTrials.gov have examined CaP materials in bone repair applications.

FIG. 8.

Trends in calcium phosphate research. (A) Annual scientific production of calcium phosphate-related articles. (B) Relative interest in calcium phosphate research, expressed as the ratio of calcium phosphate articles to total bone regeneration studies per year. (C) Global interest rate in calcium phosphate. (D) Pie chart demonstrating the distribution of bone types in calcium phosphate studies. (E) Pie chart illustrating the distribution of animal models for calcium phosphate research.

Bioactive glasses

This section encompasses all types of bioactive glass, including silicate-, borate-, and phosphate-based variants. Research into bioactive glass for bone regeneration has demonstrated a steady, incremental growth pattern. The period between 2011 and 2019 saw a steady increase, reaching its peak in 2019; after that, research declined in 2020 and 2021 but experienced renewed growth in 2023 and 2024. Finland had the highest percentage of its bone regeneration studies dedicated to bioactive glass, followed by Portugal, Iran, Egypt, and Slovakia. The studies primarily focused on long bones, with the maxillofacial regions also frequently included. In animal research, rats were the most commonly used small animals, with mice in second position. Among large animals, dogs were most prevalent, followed by sheep and goats (Fig. 9). Thirteen clinical trials have been identified to assess the effectiveness of bioactive glass in bone repair.

FIG. 9.

Trends in bioactive glass research. (A) Annual scientific production of bioactive glass-related articles. (B) Relative interest in bioactive glass research, expressed as the ratio of bioactive glass articles to total bone regeneration studies per year. (C) Global interest rate in bioactive glass. (D) Distribution of bone types in bioactive glass studies. (E) Distribution of animal models for bioactive glass research.

Silicate bioactive glasses

The most popular bioactive glass is silicate-based glass.¹⁷ Research on silicate bioactive glasses has generally shown an upward trend, although growth has decelerated over the past decade. A temporary decline post-2017 persisted until 2021, after which a resurgence was noted within the past 2 years. Finland has demonstrated the most significant research interest in this material, with Portugal, Iran, Slovakia, and Egypt trailing behind. The majority of investigations focused on long bones, along with the maxillofacial regions. In animal studies, rats represented the primary model, followed in frequency by mice. Large animal studies most commonly involved dogs, with sheep and goats also appearing frequently (Fig. 10). Furthermore, six clinical trials have explored the use of silicate bioactive glasses for bone regeneration purposes.

FIG. 10.

Trends in silicate bioactive glass research. (A) Annual scientific production of silicate bioactive glass-related articles. (B) Relative interest in silicate bioactive glass research, expressed as the ratio of silicate bioactive glass articles to total bone regeneration studies per year. (C) Global interest rate in silicate bioactive glass. (D) Distribution of bone types in silicate bioactive glass studies. (E) Distribution of animal models for silicate bioactive glass studies.

Doped bioactive glasses

Research on doped bioactive glasses for bone regeneration grew rapidly. Despite a slight decline in 2021, this area appears to be one of the fastest-growing in bone regeneration. Slovakia, Portugal, Iran, Finland, and Ukraine showed the highest percentage of studies on this material relative to their total bone research. Studies primarily targeted long bones as well as the maxillofacial regions. Animal models most frequently involved rats and mice among small animals, while large model studies included dogs followed by sheep and goats (Fig. 11). No trials were found in ClinicalTrials.gov.

FIG. 11.

Trends in doped bioactive glass research. (A) Annual scientific production of doped bioactive glass-related articles. (B) Relative interest in doped bioactive glass research, expressed as the ratio of doped bioactive glass articles to total bone regeneration studies per year. (C) Global interest rate in doped bioactive glass. (D) Distribution of bone types in doped bioactive glass studies. (E) Distribution of animal models for doped bioactive glass studies.

Natural polymers

Silk fibroin

Research on silk fibroin gained momentum after 2004 and expanded considerably, hitting a high point in 2016 and 2017 before experiencing a minor decline. Despite this, overall interest has continued to grow recently. Thailand was the leading country in interest rate, with Portugal, Iran, Singapore, and China following. Publications showed a slight preference for the calvarial region and then long bones. Small animal model research mostly used rats followed by mice, whereas large animal experiments focused mainly on goats and sheep followed by dogs and horses with seven articles each (Fig. 12). There has also been one clinical trial investigating silk fibroin’s role in bone healing.

FIG. 12.

Trends in silk fibroin research. (A) Annual scientific production of silk fibroin-related articles. (B) Relative interest in silk fibroin research, expressed as the ratio of silk fibroin articles to total bone regeneration studies per year. (C) Global interest rate in silk fibroin. (D) Distribution of bone types in silk fibroin studies. (E) Distribution of animal models for silk fibroin studies.

Hyaluronic acid

Scientific production on hyaluronic acid grew consistently from 2000 to 2024, especially in recent years. Iraq, Ireland, South Korea, Portugal, and Singapore had the highest articles relative to their total bone regeneration output. The majority of studies focused on long bones followed by the maxillofacial regions. Among animal models, rats and then rabbits were the most frequently used, while large animal studies commonly involved dogs and pigs, respectively (Fig. 13). Moreover, there have been 37 clinical trials exploring hyaluronic acid in bone healing procedures.

FIG. 13.

Trends in hyaluronic acid research. (A) Annual scientific production of hyaluronic acid-related articles. (B) Relative interest in hyaluronic acid research, expressed as the ratio of hyaluronic acid articles to total bone regeneration studies per year. (C) Global interest rate in hyaluronic acid. (D) Distribution of bone types in hyaluronic acid studies. (E) Distribution of animal models for hyaluronic acid studies.

Collagen

Collagen remains a key biomaterial in bone regeneration, although its peak research attention appears to have occurred between 2016 and 2019, and research attention has declined since then, with a slight recovery in 2023–2024. Ireland showed the highest research focus, followed by Romania, South Korea, Switzerland, and Colombia. Studies primarily examined the maxillofacial region and long bones. Additionally, 231 clinical trials have been found that explored collagen for bone repair. The distribution of bone types and animal models is illustrated in Figure 14.

FIG. 14.

Trends in collagen research. (A) Annual scientific production of collagen-related articles. (B) Relative interest in collagen research, expressed as the ratio of collagen articles to total bone regeneration studies per year. (C) Global interest rate in collagen. (D) Distribution of bone types in collagen studies. (E) Distribution of animal models for collagen studies.

Gelatin

Gelatin has shown consistent growth and remains a highly trending biomaterial in bone regeneration research from 2000 to 2024. Iran demonstrated the highest research interest, followed by Indonesia, China, Iraq, and South Korea. Studies primarily examined long bones as well as the maxillofacial regions. Animal model investigations frequently involved rats and then mice, while large animal studies commonly included pigs followed by dogs (Fig. 15). Additionally, 10 clinical trials have been registered in ClinicalTrials.gov on the use of gelatin for bone repair.

FIG. 15.

Trends in gelatin research. (A) Annual scientific production of gelatin-related articles. (B) Relative interest in gelatin research, expressed as the ratio of gelatin articles to total bone regeneration studies per year. (C) Global interest rate in gelatin. (D) Distribution of bone types in gelatin studies. (E) Distribution of animal models for gelatin studies.

Chondroitin sulfate

Over the study period, interest in chondroitin sulfate experienced fluctuations, which is expected due to the low publication volume, peaking in 2021 after a decline in 2017–2018, with recent years showing positive growth. Ukraine demonstrated the highest research focus, followed by Portugal, Ireland, Indonesia, and New Zealand. Studies primarily examined long bones along with the vertebrae. Among animal models, rats and mice were the most frequently used (Fig. 16), while large animal studies commonly involved dogs and pigs (23 articles each). No clinical trials were found investigating chondroitin sulfate for bone repair.

FIG. 16.

Trends in chondroitin sulfate research. (A) Annual scientific production of chondroitin sulfate-related articles. (B) Relative interest in chondroitin sulfate research, expressed as the ratio of chondroitin sulfate articles to total bone regeneration studies per year. (C) Global interest rate in chondroitin sulfate. (D) Distribution of bone types in chondroitin sulfate studies. (E) Distribution of animal models for chondroitin sulfate studies.

Polysaccharide-based polymers

Chitosan

During the analysis period, research on chitosan for bone regeneration expanded rapidly, positioning it among the fastest-growing biomaterials in the field. Indonesia showed the highest research focus, followed by Portugal, Iran, Malaysia, and Thailand. Studies primarily examined long bones alongside the maxillofacial regions. Animal model investigations frequently involved rats and mice, while large animal studies commonly included dogs, followed by goats and sheep (Fig. 17). Eight clinical trials have explored chitosan for bone repair.

FIG. 17.

Trends in chitosan research. (A) Annual scientific production of chitosan-related articles. (B) Relative interest in chitosan research, expressed as the ratio of chitosan articles to total bone regeneration studies per year. (C) Global interest rate in chitosan. (D) Distribution of bone types in chitosan studies. (E) Distribution of animal models for chitosan studies.

Alginate

Research on alginate for bone regeneration expanded consistently in the 2000–2024 period, with notable growth since 2018 and a significant increase in 2024 compared with the previous year. Portugal exhibited the highest percentage of alginate studies, followed by Iran, Ireland, Malaysia, and Romania. Studies primarily targeted long bones followed by the maxillofacial regions. Animal model investigations frequently involved rats and mice, while large animal studies commonly included pigs followed by dogs (Fig. 18). Additionally, five clinical trials were identified that examined alginate for bone repair.

FIG. 18.

Trends in alginate research. (A) Annual scientific production of alginate-related articles. (B) Annual percentage of alginate research to total bone regeneration studies. (C) Global interest rate in alginate. (D) Distribution of bone types in alginate studies. (E) Distribution of animal models for alginate studies.

Dextran

Overall, dextran has a low number of articles, leading to fluctuations. After some decline post-2020, research activity had a sharp resurgence in 2023 and 2024. Singapore showed the highest interest rate, followed by Iraq, Portugal, France, and South Africa. An overview of bone type distribution and animal model usage is provided in Figure 19.

FIG. 19.

Trends in dextran research. (A) Annual scientific production of dextran-related articles. (B) Relative interest in dextran research, expressed as the ratio of dextran articles to total bone regeneration studies per year. (C) Global interest rate in dextran. (D) Distribution of bone types in dextran studies. (E) Distribution of animal models for dextran studies.

Cellulose

Research activity on cellulose continued to experience strong and accelerating growth in both research output and scientific interest from 2000 to 2024, maintaining a clear upward trend. Egypt showed the highest research focus, followed by Romania, Pakistan, Malaysia, and Iran. The classification of bone types and animal models is shown in Figure 20.

FIG. 20.

Trends in cellulose research. (A) Annual scientific production of cellulose-related articles. (B) Relative interest in cellulose research. (C) Global interest rate in cellulose. (D) Distribution of bone types in cellulose studies. (E) Distribution of animal models for cellulose studies.

Synthetic polymers

Cellulose derivatives

Within the selected years, research on cellulose derivatives (e.g., ethyl, methyl, and carboxymethyl cellulose) experienced fluctuations, with a notable growth in the past 2 years. Pakistan demonstrated the highest research focus, followed by Indonesia, Portugal, Saudi Arabia, and Thailand. Studies primarily examined the maxillofacial region, followed by long bones. Animal model investigations frequently involved rats and mice, while large animal studies mainly included dogs (Fig. 21). No clinical trials were recorded.

FIG. 21.

Trends in cellulose derivatives research. (A) Annual scientific production of cellulose derivatives-related articles. (B) Relative interest in cellulose derivatives research. (C) Global interest rate in cellulose derivatives. (D) Distribution of bone types in cellulose derivatives studies. (E) Distribution of animal models for cellulose derivatives studies.

Polyhydroxybutyrate

From 2000 to 2024, research on polyhydroxybutyrate (PHB) for bone regeneration expanded but has recently declined. Overall, PHB has a low number of publications, leading to fluctuations in its trends. Iran, Slovakia, Malaysia, Singapore, and Russia had the highest interest rates in PHB, respectively. Studies primarily examined long bones alongside the calvarial region. Among animal models, rats and mice were most commonly used, while large animal studies mostly used dogs, followed by pigs (Fig. 22). No clinical trials were found in ClinicalTrials.gov.

FIG. 22.

Trends in polyhydroxybutyrate research. (A) Annual scientific production of polyhydroxybutyrate-related articles. (B) Relative interest in polyhydroxybutyrate research, expressed as the ratio of polyhydroxybutyrate articles to total bone regeneration studies per year. (C) Global interest rate in polyhydroxybutyrate. (D) Distribution of bone types in polyhydroxybutyrate studies. (E) Distribution of animal models for polyhydroxybutyrate studies.

Poly(methyl methacrylate)

Poly(methyl methacrylate) (PMMA) is widely utilized as a bone cement to enhance screw fixation during orthopedic procedures and is also used as a filler for various bone cavities and defects. Additionally, PMMA’s application extends further as a bone substitute promoting bone regeneration and growth.¹⁸ Research regarding PMMA for bone regeneration persisted relatively steadily from 2000 to 2024, but a clear decrease has been noted since 2021. Iraq, Romania, Argentina, Singapore, and Switzerland demonstrated the highest attention to this field relative to their overall bone regeneration research. The variation in bone types studied and the animal models used is illustrated in Figure 23.

FIG. 23.

Trends in poly(methyl methacrylate) (PMMA) research. (A) Annual scientific production of PMMA-related articles. (B) Relative interest in PMMA research, expressed as the ratio of PMMA articles to total bone regeneration studies per year. (C) Global interest rate in PMMA. (D) Distribution of bone types in PMMA studies. (E) Distribution of animal models for PMMA studies.

Polylactic acid

Polylactic acid (PLA) research appears to be plateauing; however, the field experienced a drop in 2022, followed by a recovery in the past 2 years. Iran, Finland, Singapore, Norway, and China demonstrated the highest research interest relative to their total bone studies. Investigations primarily examined long bones as well as the maxillofacial regions. Animal models frequently involved rats followed by rabbits, while large animal studies commonly used dogs, followed by goats and sheep (Fig. 24). Four clinical trials were identified in ClinicalTrials.gov on the exploration of PLA for bone repair.

FIG. 24.

Trends in polylactic acid research. (A) Annual scientific production of polylactic acid-related articles. (B) Relative interest in polylactic acid research. (C) Global interest rate in polylactic acid. (D) Distribution of bone types in polylactic acid studies. (E) Distribution of animal models for polylactic acid studies.

Polylactic-co-glycolic acid

Over the period from 2000 to 2024, research on polylactic-co-glycolic acid (PLGA) for bone regeneration expanded steadily, though its research momentum has tapered off since 2017 with a modest rebound in 2024. Serbia, Singapore, China, South Korea, and the Netherlands had the highest interest relative to their total bone regeneration studies. Figure 25 illustrates the patterns observed in bone types and animal models across studies.

FIG. 25.

Trends in polylactic-co-glycolic acid (PLGA) research. (A) Annual scientific production of PLGA-related articles. (B) Relative interest in PLGA research, expressed as the ratio of PLGA articles to total bone regeneration studies per year. (C) Global interest rate in PLGA. (D) Distribution of bone types in PLGA studies. (E) Distribution of animal models for PLGA studies.

Polycaprolactone

Research on polycaprolactone (PCL) for bone regeneration demonstrated one of the most robust long-term growth patterns among biomaterials. Singapore, Iran, Portugal, South Korea, and Thailand led in the proportion of research dedicated to PCL. The dominant focus was on long bones, with calvarial regions also frequently studied. In terms of animal models, rats and mice were most often employed in small animal research, while large animal studies primarily involved goats and sheep, followed by pigs (Fig. 26). Additionally, eight clinical trials examining PCL’s applications in bone repair have been identified.

FIG. 26.

Trends in polycaprolactone (PCL) research. (A) Annual scientific production of PCL-related articles. (B) Relative interest in PCL research. (C) Global interest rate in PCL. (D) Distribution of bone types in PCL studies. (E) Distribution of animal models for PCL studies.

Polyethylene glycol

Polyethylene glycol (PEG) research peaked in 2018 and then declined. While PEG research has not returned to its 2018 peak, the recent 2-year data indicate a renewed, modest, upward momentum. Indonesia, Ireland, the Netherlands, Switzerland, and Singapore showed the highest research focus relative to total bone regeneration studies. Figure 27 displays the distribution of bone types and the animal models employed. Two clinical trials investigating PEG for bone repair were found on ClinicalTrials.gov.

FIG. 27.

Trends in polyethylene glycol research. (A) Annual scientific production of polyethylene glycol-related articles. (B) Relative interest in polyethylene glycol research. (C) Global interest rate in polyethylene glycol. (D) Distribution of bone types in polyethylene glycol studies. (E) Distribution of animal models for polyethylene glycol studies.

Others

Graphene

Before 2013, research on graphene in bone regeneration was minimal. Although a downturn was observed in 2023, the overall trend for this material has been positive. Iran, Iraq, Malaysia, Romania, and Saudi Arabia displayed the highest proportional focus on graphene research within their overall bone regeneration efforts. The distribution across bone types was fairly even, with particular emphasis on long bones and calvarial regions. In animal models, rats and mice were predominant, while large animal studies were scarce and mainly involved dogs (Fig. 28). No clinical trials have been found to explore graphene’s efficacy in bone repair.

FIG. 28.

Trends in graphene research. (A) Annual scientific production of graphene-related articles. (B) Relative interest in graphene research, expressed as the ratio of graphene articles to total bone regeneration studies per year. (C) Global interest rate in graphene. (D) Distribution of bone types in graphene studies. (E) Distribution of animal models for graphene studies.

Polydopamine

Before 2010, no research articles on polydopamine for bone regeneration were found. Research on polydopamine expanded rapidly, establishing it as a fast-growing material in bone regeneration research, especially from 2020 onward. China demonstrated both the highest number of publications and the strongest interest rate, followed by Singapore, South Korea, Iran, and Malaysia. Figure 29 illustrates the patterns observed in bone types and animal models across studies. No clinical trials have yet evaluated polydopamine for bone repair.

FIG. 29.

Trends in polydopamine research. (A) Annual scientific production of polydopamine-related articles. (B) Relative interest in polydopamine research. (C) Global interest rate in polydopamine. (D) Distribution of bone types in polydopamine studies. (E) Distribution of animal models for polydopamine studies.

Peptide

Interest in peptide research after experiencing rapid expansion in the early 2000s, stabilized following its peak in 2010, with a modest resurgence in the past 2 years. Denmark and New Zealand exhibited the strongest research focus relative to their total output, followed closely by China, Norway, and Singapore. The classification of bone types and animal models is shown in Figure 30. Additionally, five clinical trials have explored peptide-based strategies for bone treatment.

FIG. 30.

Trends in peptide research. (A) Annual scientific production of peptide-related articles. (B) Relative interest in peptide research. (C) Global interest rate in peptide. (D) Distribution of bone types in peptide studies. (E) Distribution of animal models for peptide studies.

Calcium sulfate

The research span from 2000 to 2024 reveals that calcium sulfate for bone regeneration demonstrated moderate but steady growth, followed by a gradual decline in interest since 2014. Sweden, Indonesia, and China showed the highest research emphasis relative to their total output. Figure 31 presents the distribution of bone defect types and animal models. Additionally, 20 clinical trials were found on this topic in ClinicalTrials.gov.

FIG. 31.

Trends in calcium sulfate research. (A) Annual scientific production of calcium sulfate-related articles. (B) Relative interest in calcium sulfate research. (C) Global interest rate in calcium sulfate. (D) Distribution of bone types in calcium sulfate studies. (E) Distribution of animal models for calcium sulfate studies.

Calcium carbonate

Research on calcium carbonate experienced steady growth, though interest declined over the past 5 years with signs of recovery in 2023. Indonesia, Malaysia, Iraq, Thailand, and Morocco showed the highest proportional focus, while China and the United States led in publication volume but ranked lower in relative emphasis. Studies mainly targeted long bones, followed by the vertebrae. Animal model investigations were balanced between rats and mice, with large animal research involving dogs, followed by goats and sheep (Fig. 32). Three clinical trials have explored calcium carbonate for bone repair in ClinicalTrials.gov.

FIG. 32.

Trends in calcium carbonate research. (A) Annual scientific production of calcium carbonate-related articles. (B) Relative interest in calcium carbonate research. (C) Global interest rate in calcium carbonate. (D) Distribution of bone types in calcium carbonate studies. (E) Distribution of animal models for calcium carbonate studies.

Bone morphogenetic proteins

Bone morphogenetic proteins (BMPs) maintained a prominent role in bone regeneration research from 2000 to 2024. BMPs were once a leading topic in bone regeneration research, peaking around 2014–2015, but both publication output and scientific focus have steadily diminished since then. South Korea had the highest interest rate, followed by Croatia, Singapore, China, and Indonesia. China showed both a high publication volume and a strong relative emphasis. Research prominently targeted long bones, followed by the maxillofacial regions. Animal studies relied heavily on rats, followed by mice. In large animal models, dogs were the most frequent, followed by pigs (Fig. 33). Moreover, 25 clinical trials have explored BMPs in bone repair.

FIG. 33.

Trends in bone morphogenetic proteins (BMPs) research. (A) Annual scientific production of BMPs-related articles. (B) Relative interest in BMPs research. (C) Global interest rate in BMPs. (D) Distribution of bone types in BMPs studies. (E) Distribution of animal models for BMPs studies.

Stem cells

From 2000 to 2024, stem cells emerged as one of the most extensively studied approaches in bone regeneration, with over 21,000 publications and consistently high global interest, despite the apparent plateau in growth over recent years. China led in both volume and focus, followed by strong engagement from Iran, Singapore, Portugal, and Ireland. Research predominantly targeted long bones alongside substantial attention to the maxillofacial regions. Rodent models, particularly mice and rats, dominated preclinical investigations, while dogs and pigs were the most frequently used large animal models, respectively (Fig. 34). ClinicalTrials.gov had 208 clinical trials registered for stem cell-based bone regeneration.

FIG. 34.

Trends in stem cell research. (A) Annual scientific production of stem cell-related articles. (B) Relative interest in stem cell research. (C) Global interest rate in stem cells. (D) Distribution of bone types in stem cell studies. (E) Distribution of animal models for stem cell studies.

Exosome

From 2013 onward, research on exosomes for bone regeneration has surged, establishing them as one of the most rapidly expanding areas in regenerative medicine. China has led both in volume and research intensity, followed by Ireland, Singapore, Norway, and Egypt. Exosome studies most frequently targeted the maxillofacial region, followed by long bones. Animal studies have predominantly used rats followed by mice, but rabbits’ numbers were really low compared with mice and rats, with only 28 articles. Large animal studies have also been scarce, with only 17 studies (Fig. 35). ClinicalTrials.gov lists one trial investigating exosomes for bone repair.

FIG. 35.

Trends in exosome research. (A) Annual scientific production of exosome-related articles. (B) Relative interest in exosome research. (C) Global interest rate in exosomes. (D) Distribution of bone types in exosome studies. (E) Distribution of animal models for exosome studies.

Gene therapy

The field remained steady over the last decade, with a slight surge in 2019 and a renewed uptick in the past 2 years. China led both in volume and interest rate; Ireland, the United States, Israel, and Japan also showed high interest rates, respectively. The most frequently studied regions were the maxillofacial and long bones. The full distribution of bone defect types and animal models is shown in Figure 36. From the 3,599 clinical trials identified on ClinicalTrials.gov, 10 were investigating gene therapy strategies for bone repair.

FIG. 36.

Trends in gene therapy strategies research. (A) Annual scientific production of gene therapy strategies-related articles. (B) Relative interest in gene therapy strategies research. (C) Global interest rate in gene therapy strategies. (D) Distribution of bone types in gene therapy strategies studies. (E) Distribution of animal models for gene therapy strategies studies.

Platelet-rich plasma

Platelet-rich plasma (PRP) gained considerable attention in bone regeneration during this period. Research peaked in 2021 before dropping in 2022 and 2023, with a slight rebound in 2024, though still below the peak. PRP saw its strongest focus from 2016 to 2021, but recent data suggest a slight decline in momentum. Iraq showed the highest interest rate, followed by Indonesia, Chile, India, and Egypt. India ranked high in both total volume and interest rate. The distribution of bone types and animal models is illustrated in Figure 37. Notably, PRP ranks high in clinical translation, with 137 registered clinical trials in ClinicalTrials.gov.

FIG. 37.

Trends in platelet-rich plasma (PRP) research. (A) Annual scientific production of PRP-related articles. (B) Relative interest in PRP research. (C) Global interest rate in PRP. (D) Distribution of bone types in PRP studies. (E) Distribution of animal models for PRP studies.

Several additional biomaterials were initially considered for inclusion in this review; however, each yielded fewer than 300 relevant publications and was therefore excluded from further analysis. Among CaP-based materials, tetracalcium phosphate was represented by only 55 articles, with the highest annual count being 5 in both 2021 and 2023. In the category of bioactive glasses, borate bioactive glasses accounted for 218 articles (0.07% of all bone repair studies), with a peak of 27 publications in 2024. Natural polymers such as fibrin (279 articles), gellan gum (97 articles), carrageenan (75 articles), and keratin (49 articles) also fell below the inclusion threshold. Similarly, synthetic polymers including poly(butylene succinate) (35 articles), poly(ethylene terephthalate) (15 articles), and poly(butylene adipate-co-terephthalate) (17 articles) were also excluded due to insufficient publication volume. As a result, no further analysis was conducted for these materials.

Results Overview

This overview summarizes the combined analysis of all materials discussed in this study (Fig. 38). The overall trend indicates a plateau after 2014. Portugal, Indonesia, Iran, China, and Singapore exhibited the highest focus on these materials, with each dedicating more than approximately 30% of their total bone treatment research to them. Studies targeting the maxillofacial region and the hind limb (femur and tibia) each constituted about 30% of the total articles. Among animal models, nearly two-thirds involved rats and mice, with rabbits accounting for about half of the remaining third. Additionally, Figure 39 illustrates the year-by-year publication trends encompassing all biomaterial approaches analyzed in this study. A comprehensive summary of data for all mentioned biomaterials is presented in Table 1. Additionally, an overview of the top contributing countries and model applications is provided in Table 2.

FIG. 38.

Trends in all biomaterials or regenerative strategies included in this study. (A) Annual scientific production of biomaterials. (B) Relative research interest in biomaterials over time. (C) Global interest rate in biomaterials research. (D) Distribution of bone types examined across biomaterial studies. (E) Distribution of animal models employed in biomaterial evaluations.

FIG. 39.

Annual scientific production across all investigated biomaterials and strategies. BG, bioactive glass; CaP, calcium phosphate; HA, hydroxyapatite; PDA, polydopamine; PEG, polyethylene glycol; PHB, polyhydroxybutyrate; PLA, polylactic acidSS.

Table 1.

Summary of All Data

	Total articles	% of all bone studies	Peak years	Publication GR (%) (2000–2024)	Overall publication AAGR (%) (2000–2024)	Overall interest rate GR (%) (2000–2024)	Interest rate AAGR (%) (2000–2024)	Ten-year interest rate AAGR (%) (2015–2024)	Five-year interest rate AAGR (%) (2020–2024)	Two-year interest rate AAGR (%) (2023–2024)	Total animal studies	Large animal studies	Large animal model (%)	Clinical trials
HA	14,976	4.58	2016 and 2017	656.86	9.47	69.13	2.62	0.38	2.16	3.36	7,097	1,175	16.56	70
DCP	620	0.19	2022 (with fluctuations)	47.37	11.70	−67.07	5.23	3.00	1.03	−19.81	283	70	24.73	1
TCP	5,389	1.65	2014–2018	609.30	10.14	58.50	3.25	−4.00	−4.02	0.30	3,092	752	24.32	60
OCP	328	0.10	2022	500.00	33.07	46.43	23.89	5.96	5.00	−31.94	174	29	16.67	5
BCP	2,632	0.81	2015 and 2016	625.00	11.26	62.01	4.14	−3.09	−2.15	0.39	1,536	376	24.48	33
Calcium phosphate	23,893	7.31	2016	707.48	9.89	80.44	3.00	−0.67	0.14	1.72	11,435	2,106	18.42	161
Bioactive glass	3,586	1.10	2019	766.67	10.82	93.67	3.92	1.36	0.31	7.25	2,306	127	5.51	13
Silicate BG	2,097	0.64	2017	472.41	9.02	27.91	2.40	0.55	−0.13	10.34	756	71	9.39	6
Doped BG	1,037	0.32	2024 (ongoing peak)	2,620.00	30.18	507.82	22.08	9.49	4.89	14.80	346	25	7.23	9
Silk fibroin	883	0.27	2016 and 2017	3,100.00	22.32	807.17	14.70	9.03	1.00	2.43	538	27	5.02	1
Hyaluronic acid	1,689	0.52	2024 (ongoing peak)	1,754.55	20.99	314.42	13.34	7.07	9.70	22.53	1,003	166	16.55	37
Collagen	5,785	1.77	2016–2019	687.50	9.82	75.98	3.03	−1.30	−4.51	1.52	3,664	920	25.11	231
Gelatin	4,119	1.26	2024 (ongoing peak)	2,152.17	14.55	403.28	7.41	7.54	9.40	11.57	2,495	230	9.22	10
Chondroitin sulfate	485	0.15	2004 and 2021 (fluctuating)	414.29	16.01	14.92	8.81	2.28	5.56	4.69	308	67	21.75	0
Chitosan	3,504	1.07	2024 (ongoing peak)	4,800.00	28.49	994.97	20.29	4.22	3.76	8.65	1,871	163	8.71	8
Alginate	1,879	0.58	2024 (ongoing peak)	3,414.29	18.75	685.31	11.10	7.32	12.88	13.24	996	103	10.34	5
Dextran	314	0.10	2002 and 2024 (fluctuating)	400.00	14.91	11.73	8.14	8.78	8.37	40.99	176	19	10.80	0
Cellulose	947	0.29	2024 (ongoing peak)	5,450.00	30.88	1,140.22	22.31	8.39	8.68	19.00	338	46	13.61	7
Cellulose derivates	326	0.10	2023 (with fluctuations)	966.67	18.18	138.36	11.20	8.10	1.61	20.00	163	30	18.40	0
PHB	356	0.11	2009 and 2022–2023 (fluctuating)	2,600.00	29.78	503.35	21.23	1.49	0.06	−6.21	161	14	8.70	0
PMMA	2,056	0.63	2021	200.00	5.97	−32.96	−0.36	−1.36	−4.61	−16.65	625	161	25.76	8
PLA	3,885	1.19	2005	458.49	8.69	24.80	1.87	1.10	2.21	15.45	2,014	304	15.09	4
PLGA	2,390	0.73	2014	552.17	10.61	45.74	3.44	−3.00	−1.50	1.71	1,559	197	12.64	5
PCL	3,305	1.01	2024 (ongoing peak)	9,250.00	23.99	1,989.38	16.25	3.96	4.49	4.36	1,675	229	13.67	8
PEG	1,518	0.46	2018	2,740.00	16.81	534.63	9.83	2.01	1.67	7.05	823	109	13.24	2
Graphene	720	0.22	2022 and 2024 (ongoing peak)	1,800.00	39.79	1,028.96	32.15	20.72	5.69	3.15	305	12	3.93	0
PDA	503	0.15	2024 (ongoing peak)	4,600.00	68.75	2,162.02	57.29	24.26	9.29	10.07	297	8	2.69	0
Peptide	4,368	1.34		1,029.03	12.03	152.30	5.22	1.89	1.81	6.42	2,500	207	8.28	5
Calcium sulfate	1,115	0.34	—	688.89	13.85	76.29	6.85	−2.62	−0.27	−4.01	454	85	18.72	20
Calcium carbonate	1,056	0.32	—	464.29	16.40	26.10	9.88	6.03	0.54	6.29	376	49	13.03	3
BMP	8,521	2.61	2014–2015	490.67	8.54	31.99	1.76	−5.32	−7.26	−3.57	6,343	813	12.82	25
Stem cells	21,707	6.64	2018–2019	3,710.00	17.33	751.39	10.06	1.28	−0.74	2.65	14,408	1,525	10.58	208
Exosome	781	0.24	2024 (ongoing peak)	9,500.00	113.14	5,604.22	106.67	108.85	25.30	14.04	557	17	3.05	1
Gene therapy	3,848	1.18	—	783.33	10.60	97.39	3.68	1.79	0.86	9.27	2,756	169	6.13	10
PRP	2,917	0.89	—	2,533.33	16.51	488.45	9.38	2.44	−2.19	0.53	1,133	313	27.63	137

Table values are displayed with color gradients to indicate magnitude and direction. Green shades denote increasingly positive values, and red shades denote increasingly negative values. Separately, the first column indicates the number of articles per biomaterial; biomaterials with fewer than 500 publications are shaded yellow to highlight that those results should be interpreted cautiously due to limited data.

AAGR, annual average growth rate; BCP, biphasic calcium phosphate; BMP, bone morphogenetic proteins; DCP, dicalcium phosphate; Doped BG, doped bioactive glass; GR, growth rate; HA, hydroxyapatite; OCP, octacalcium phosphate; PCL, polycaprolactone; PDA, polydopamine; PEG, polyethylene glycol; PHB, polyhydroxybutyrate; PLA, polylactic acid; PLGA, polylactic-co-glycolic acid; PMMA, poly(methyl methacrylate); PRP, platelet-rich plasma; Silicate BG, silicate bioactive glass; TCP, tricalcium phosphate.

Table 2.

Overview of Top Countries and Model Applications

	Country’s article volume	Country’s interest rate	Bone-specific publications	Animal models
HA	1. China (3,948)2. United States (2,047)3. Japan (1,073)4. India (979)5. Germany (872)	1. Indonesia (15.78%)2. Malaysia (12.91%)3. Iran (11.50%)4. Portugal (11.03%)5. Romania (10.71%)	1. Long bones (3,009)- Femur (1,671)- Tibia (862)2. Maxillofacial (2,210)3. Calvarial (1,500)4. Vertebrae (767)	Small animal models (5,373)1. Mice (3,496)2. Rat (1,749)3. Rabbit (128)Large animal models (1,175)1. Dog (524)2. Goat and sheep (355)3. Pig (278)
DCP	1. China (119)2. United States (100)3. Germany (76)4. Japan (45)5. Spain (34)	1. Morocco (0.63%)2. Russia (0.57%)3. Iraq (0.50%)4. Iran (0.49%)5. Indonesia (0.49%)	1. Long bones (125)- Femur (73)- Tibia (37)2. Calvarial (56)3. Maxillofacial (50)4. Vertebrae (36)	Small animal models (196)1. Rabbit (86)2. Rat (64)3. Mice (59)Large animal models (70)1. Dog (17)2. Pig (12)3. Goat and sheep (11)
TCP	1. China (1,468)2. United States (713)3. Japan (636)4. Germany (497)5. South Korea (382)	1. Singapore (3.67%)2. Iraq (3.64%)3. Ukraine (3.54%)4. Portugal (3.44%)5. Hungary (3.24%)	1. Long bones (1,212)- Femur (632)- Tibia (349)2. Maxillofacial (1,160)3. Calvarial (650)4. Vertebrae (303)	Small animal models (2,221)1. Rat (963)2. Rabbit (852)3. Mice (593)Large animal models (752)1. Dog (380)2. Goat and sheep (219)3. Pig (150)
OCP	1. Japan (133)2. China (59)3. United States (33)4. Russia (31)5. South Korea (17)	1. Russia (0.80%)2. Japan (0.63%)3. Croatia (0.24%)4. Mexico (0.23%)5. Iran (0.22%)	1. Calvarial (65)2. Long bones (62)- Femur (27)- Tibia (22)3. Maxillofacial (34)4. Vertebrae (2)	Small animal models (149)1. Rat (82)2. Mice (50)3. Rabbit (29)Large animal models (29)1. Dog (17)2. Pig (12)3. Goat and sheep (1)
BCP	1. China (532)2. United States (321)3. South Korea (304)4. Germany (213)5. Japan (192)	1. South Korea (2.52%)2. Iraq (2.48%)3. Portugal (2.31%)4. Ukraine (2.23%)5. Malaysia (2.16%)	1. Maxillofacial (556)2. Long bones (458)- Femur (250)- Tibia (130)3. Calvarial (352)4. Vertebrae (122)	Small animal models (1,084)1. Rat (430)2. Rabbit (411)3. Mice (331)Large animal models (376)1. Dog (183)2. Goat and sheep (110)3. Pig (81)
Calcium phosphate	1. China (6,887)2. United States (3,433)3. Japan (1,950)4. Germany (1,609)5. South Korea (1,340)	1. Indonesia (18.04%)2. Portugal (17.81%)3. Malaysia (16.52%)4. Iran (15.52%)5. Romania (13.90%)	1. Long bones (5,849)- Femur (3,417)- Tibia (1,549)2. Maxillofacial (3,709)3. Calvarial (2,432)4. Vertebrae (1,706)	Small animal models (8,560)1. Rat (3,819)2. Rabbit (2,862)3. Mice (2,710)Large animal models (2,106)1. Dog (970)2. Goat and sheep (642)3. Pig (456)
Bioactive glass	1. China (978)2. United States (390)3. Germany (370)4. United Kingdom (352)5. India (264)	1. Finland (7.58%)2. Portugal (4.76%)3. Iran (4.36%)4. Egypt (3.26%)5. Slovakia (2.90%)	1. Long bones (526)- Femur (230)- Tibia (158)2. Maxillofacial (486)3. Calvarial (247)4. Vertebrae (89)	Small animal models (1,082)1. Rat (552)2. Mice (340)3. Rabbit (312)Large animal models (127)1. Dog (66)2. Goat and sheep (30)3. Pig (19)
Silicate BG	1. China (472)2. Germany (250)3. United Kingdom (233)4. United States (229)5. Brazil (155)	1. Finland (4.91%)2. Portugal (3.11%)3. Iran (2.45%)4. Slovakia (1.99%)5. Egypt (1.95%)	1. Long bones (313)- Femur (139)- Tibia (93)2. Maxillofacial (216)3. Calvarial (131)4. Vertebrae (53)	Small animal models (621)1. Rat (316)2. Mice (191)3. Rabbit (182)Large animal models (71)1. Dog (35)2. Goat and sheep (20)3. Pig (7)
Doped BG	1. China (264)2. Germany (131)3. United Kingdom (103)4. Italy (99)5. United States (89)	1. Slovakia (1.99%)2. Portugal (1.84%)3. Iran (1.66%)4. Finland (1.38%)5. Ukraine (1.21%)	1. Long bones (137)- Femur (64)- Radius (28)- Tibia (26)2. Maxillofacial (135)3. Calvarial (50)4. Vertebrae (10)	Small animal models (305)1. Rat (161)2. Mice (125)3. Rabbit (59)Large animal models (25)1. Dog (9)2. Goat and sheep (8)3. Pig (3)
Silk fibroin	1. China (477)2. United States (79)3. India (77)4. South Korea (62)5. Iran (53)	1. Thailand (1.84%)2. Portugal (1.32%)3. Iran (0.99%)4. Singapore (0.94%)5. China (0.79%)	1. Calvarial (110)2. Long bones (108)- Femur (61)- Tibia (23)3. Maxillofacial (85)4. Vertebrae (18)	Small animal models (438)1. Rat (228)2. Mice (148)3. Rabbit (117)Large animal models (27)1. Goat and sheep (14)2. Horse (7)3. Dog (7)
Hyaluronic acid	1. China (452)2. United States (317)3. Italy (136)4. South Korea (128)5. Germany (116)	1. Iraq (1.32%)2. Ireland (1.08%)3. South Korea (1.06%)4. Portugal (1.04%)5. Singapore (1.00%)	1. Long bones (518)- Femur (330)- Tibia (169)2. Maxillofacial (441)3. Calvarial (177)4. Vertebrae (85)	Small animal models (754)1. Rat (347)2. Rabbit (252)3. Mice (245)Large animal models (166)1. Dog (55)2. Pig (53)3. Goat and sheep (51)
Collagen	1. China (1,301)2. United States (1,271)3. Germany (523)4. Italy (484)5. Japan (471)	1. Ireland (5.66%)2. Romania (3.93%)3. South Korea (3.77%)4. Switzerland (3.42%)5. Colombia (3.34%)	1. Maxillofacial (2,232)2. Long bones (1,019)- Femur (591)- Tibia (280)3. Calvarial (797)4. Vertebrae (350)	Small animal models (2,414)1. Rat (1,270)2. Rabbit (696)3. Mice (681)Large animal models (920)1. Dog (469)2. Pig (350)3. Goat and sheep (125)
Gelatin	1. China (1,639)2. United States (723)3. Japan (368)4. Iran (272)5. South Korea (225)	1. Iran (5.09%)2. Indonesia (3.88%)3. China (2.70%)4. Iraq (2.31%)5. South Korea (1.87%)	1. Long bones (876)- Femur (481)- Tibia (218)2. Maxillofacial (803)3. Calvarial (645)4. Vertebrae (277)	Small animal models (2,120)1. Rat (1,052)2. Mice (921)3. Rabbit (389)Large animal models (230)1. Pig (98)2. Dog (92)3. Goat and sheep (32)
Chondroitin sulfate	1. United States (121)2. China (107)3. Germany (57)4. Japan (44)5. United Kingdom (41)	1. Ukraine (0.40%)2. Portugal (0.38%)3. Ireland (0.36%)4. Indonesia (0.32%)5. New Zealand (0.27%)	1. Long bones (168)- Femur (97)- Tibia (59)2. Vertebrae (82)3. Maxillofacial (70)4. Calvarial (52)	Small animal models (210)1. Rat (114)2. Mice (75)3. Rabbit (38)Large animal models (67)1. Dog (23)2. Pig (23)3. Goat and sheep (19)
Chitosan	1. China (1,520)2. United States (348)3. India (299)4. Iran (240)5. South Korea (165)	1. Indonesia (5.66%)2. Portugal (4.95%)3. Iran (4.49%)4. Malaysia (3.18%)5. Thailand (2.87%)	1. Long bones (488)- Femur (244)- Tibia (128)2. Maxillofacial (461)3. Calvarial (329)4. Vertebrae (64)	Small animal models (1,577)1. Rat (788)2. Mice (584)3. Rabbit (379)Large animal models (163)1. Dog (76)2. Goat and sheep (43)3. Pig (34)
Alginate	1. China (674)2. United States (282)3. India (138)4. Germany (127)5. South Korea (123)	1. Portugal (2.59%)2. Iran (2.30%)3. Ireland (1.63%)4. Malaysia (1.38%)5. Romania (1.36%)	1. Long bones (311)- Femur (187)- Tibia (66)2. Maxillofacial (310)3. Calvarial (212)4. Vertebrae (60)	Small animal models (816)1. Rat (428)2. Mice (297)3. Rabbit (207)Large animal models (103)1. Pig (35)2. Dog (33)3. Goat and sheep (28)
Dextran	1. China (99)2. United States (71)3. Japan (23)4. France (21)5. Italy (16)	1. Singapore (0.47%)2. Iraq (0.33%)3. Portugal (0.33%)4. France (0.18%)5. South Africa (0.18%)	1. Long bones (127)- Femur (68)- Tibia (34)2. Maxillofacial (69)3. Vertebrae (27)4. Calvarial (24)	Small animal models (143)1. Rat (76)2. Mice (70)3. Rabbit (18)Large animal models (19)1. Dog (8)2. Pig (5)3. Goat and sheep (3)
Cellulose	1. China (253)2. United States (135)3. India (86)4. South Korea (63)5. Iran (47)	1. Egypt (1.10%)2. Romania (1.08%)3. Pakistan (0.98%)4. Malaysia (0.90%)5. Iran (0.88%)	1. Calvarial (150)2. Long bones (129)- Femur (64)- Radius (31)3. Maxillofacial (119)4. Vertebrae (47)	Small animal models (263)1. Rat (127)2. Mice (103)3. Rabbit (61)Large animal models (46)1. Dog (20)2. Goat and sheep (14)3. Pig (9)
Cellulose derivates	1. China (75)2. United States (49)3. India (36)4. France (25)5. South Korea (23)	1. Pakistan (0.56%)2. Indonesia (0.49%)3. Portugal (0.42%)4. Saudi Arabia (0.34%)5. Thailand (0.33%)	1. Maxillofacial (52)2. Long bones (50)- Femur (31)- Tibia (10)3. Calvarial (28)4. Vertebrae (8)	Small animal models (122)1. Rat (53)2. Mice (46)3. Rabbit (33)Large animal models (30)1. Dog (19)2. Goat and sheep (5)3. Pig (4)
PHB	1. China (117)2. Iran (57)3. Germany (28)4. Brazil (26)5. Russia (22)	1. Iran (1.07%)2. Slovakia (0.72%)3. Malaysia (0.60%)4. Singapore (0.58%)5. Russia (0.57%)	1. Long bones (51)- Femur (23)- Tibia (14)2. Calvarial (21)3. Maxillofacial (19)4. Vertebrae (2)5. Sternal (2)	Small animal models (133)1. Rat (64)2. Mice (43)3. Rabbit (35)Large animal models (14)1. Dog (6)2. Pig (5)3. Goat and sheep (2)
PMMA	1. United States (541)2. China (353)3. Germany (215)4. Japan (115)5. India (104)	1. Iraq (1.32%)2. Romania (1.22%)3. Argentina (1.20%)4. Singapore (1.15%)5. Switzerland (1.05%)	1. Vertebrae (1,425)2. Long bones (1,004)- Femur (546)- Tibia (311)3. Maxillofacial (307)4. Calvarial (304)	Small animal models (376)1. Rat (176)2. Rabbit (165)3. Mice (72)Large animal models (161)1. Goat and sheep (79)2. Dog (71)3. Pig (37)
PLA	1. China (1,389)2. United States (651)3. Japan (315)4. Germany (220)5. South Korea (220)	1. Iran (2.90%)2. Finland (2.80%)3. Singapore (2.62%)4. Norway (2.29%)5. China (2.29%)	1. Long bones (800)- Femur (374)- Tibia (237)2. Maxillofacial (675)3. Calvarial (463)4. Vertebrae (163)	Small animal models (1,607)1. Rat (721)2. Rabbit (532)3. Mice (521)Large animal models (304)1. Dog (138)2. Goat and sheep (95)3. Pig (66)
PLGA	1. China (995)2. United States (524)3. South Korea (179)4. Japan (150)5. Germany (110)	1. Serbia (3.09%)2. Singapore (2.25%)3. China (1.64%)4. South Korea (1.49%)5. Netherlands (1.29%)	1. Maxillofacial (479)2. Long bones (456)- Femur (258)- Tibia (89)3. Calvarial (377)4. Vertebrae (63)	Small animal models (1,316)1. Rat (640)2. Rabbit (418)3. Mice (407)Large animal models (197)1. Dog (91)2. Pig (62)3. Goat and sheep (50)
PCL	1. China (911)2. United States (550)3. South Korea (366)4. Iran (324)5. United Kingdom (205)	1. Singapore (7.50%)2. Iran (6.06%)3. Portugal (4.24%)4. South Korea (3.04%)5. Thailand (2.93%)	1. Long bones (475)- Femur (230)- Tibia (133)2. Calvarial (406)3. Maxillofacial (384)4. Vertebrae (64)	Small animal models (1,357)1. Rat (678)2. Mice (491)3. Rabbit (328)Large animal models (229)1. Goat and sheep (84)2. Dog (67)3. Pig (72)
PEG	1. China (530)2. United States (385)3. Germany (85)4. United Kingdom (83)5. Japan (77)	1. Indonesia (1.21%)2. Ireland (0.96%)3. Netherlands (0.94%)4. Switzerland (0.91%)5. Singapore (0.89%)	1. Vertebrae (344)2. Long bones (320)- Femur (161)- Tibia (75)3. Maxillofacial (238)4. Calvarial (232)	Small animal models (664)1. Rat (313)2. Mice (273)3. Rabbit (162)Large animal models (109)1. Dog (42)2. Pig (36)3. Goat and sheep (26)
Graphene	1. China (347)2. Iran (90)3. India (76)4. United States (69)5. South Korea (51)	1. Iran (1.68%)2. Iraq (1.32%)3. Malaysia (1.32%)4. Romania (1.02%)5. Saudi Arabia (0.88%)	1. Long bones (86)- Femur (33)- Radius (27)2. Calvarial (75)3. Maxillofacial (33)4. Vertebrae (4)	Small animal models (275)1. Rat (155)2. Mice (116)3. Rabbit (39)Large animal models (12)1. Dog (7)2. Goat and sheep (3)3. Pig (2)
PDA	1. China (429)2. United States (49)3. South Korea (37)4. Iran (13)5. Australia (11)	1. China (0.71%)2. Singapore (0.31%)3. South Korea (0.31%)4. Iran (0.24%)5. Malaysia (0.24%)	1. Long bones (71)- Femur (51)- Tibia (9)2. Calvarial (66)3. Maxillofacial (50)4. Vertebrae (8)	Small animal models (274)1. Rat (150)2. Mice (124)3. Rabbit (56)Large animal models (8)1. Pig (5)2. Dog (2)3. Goat and sheep (1)
Peptide	1. United States (1,331)2. China (1,293)3. Japan (390)4. Germany (352)5. United Kingdom (285)	1. Denmark (2.26%)2. New Zealand (2.17%)3. China (2.13%)4. Norway (2.02%)5. Singapore (1.94%)	1. Long bones (1,338)- Femur (875)- Tibia (326)2. Maxillofacial (1,129)3. Calvarial (519)4. Vertebrae (497)	Small animal models (2,039)1. Mice (1,104)2. Rat (925)3. Rabbit (267)Large animal models (207)1. Dog (70)2. Pig (70)3. Goat and sheep (54)
Calcium sulfate	1. China (458)2. United States (226)3. Italy (70)4. United Kingdom (63)5. India (60)	1. Sweden (0.97%)2. Indonesia (0.89%)3. China (0.75%)4. United Arab Emirates (0.68%)5. Greece (0.66%)	1. Long bones (414)- Femur (175)- Tibia (169)2. Maxillofacial (205)3. Vertebrae (134)4. Calvarial (71)	Small animal models (331)1. Rabbit (164)2. Rat (144)3. Mice (72)Large animal models (85)1. Dog (44)2. Goat and sheep (20)3. Pig (17)
Calcium carbonate	1. China (221)2. United States (164)3. Japan (91)4. Germany (88)5. Italy (66)	1. Indonesia (2.27%)2. Malaysia (1.50%)3. Iraq (0.99%)4. Thailand (0.98%)5. Morocco (0.94%)	1. Long bones (384)- Femur (277)- Radius (63)2. Vertebrae (215)3. Maxillofacial (115)4. Calvarial (58)	Small animal models (242,331)1. Rat (97)2. Mice (97)3. Rabbit (70)Large animal models (49)1. Goat and sheep (18)2. Dog (17)3. Pig (8)
BMP	1. China (2,925)2. United States (2,373)3. Japan (710)4. South Korea (695)5. Germany (638)	1. South Korea (5.77%)2. Croatia (4.87%)3. Singapore (4.82%)4. China (4.81%)5. Indonesia (4.37%)	1. Long bones (2,572)- Femur (1,396)- Tibia (746)2. Maxillofacial (1,797)3. Vertebrae (1,509)4. Calvarial (1,491)	Small animal models (5,180)1. Rat (2,415)2. Mice (2,192)3. Rabbit (1,162)Large animal models (813)1. Dog (381)2. Goat and sheep (200)3. Pig (216)
Stem cells	1. China (9,042)2. United States (4,715)3. Germany (1,402)4. Japan (1,360)5. South Korea (1,085)	1. China (14.88%)2. Iran (13.50%)3. Singapore (12.27%)4. Portugal (12.02%)5. Ireland (11.74%)	1. Long bones (5,366)- Femur (3,244)- Tibia (1,420)2. Maxillofacial (4,725)3. Calvarial (2,804)4. Vertebrae (999)	Small animal models (12,188)1. Mice (5,632)2. Rat (5,570)3. Rabbit (2,166)Large animal models (1,525)1. Dog (545)2. Pig (509)3. Goat and sheep (441)
Exosome	1. China (530)2. United States (89)3. Germany (29)4. United Kingdom (25)5. Italy (25)	1. China (0.87%)2. Ireland (0.72%)3. Singapore (0.63%)4. Norway (0.33%)5. Egypt (0.28%)	1. Maxillofacial (220)2. Long bones (187)- Femur (123)- Tibia (54)3. Calvarial (114)4. Vertebrae (28)	Small animal models (507)1. Rat (283)2. Mice (257)3. Rabbit (28)Large animal models (17)1. Dog (7)2. Pig (8)3. Goat and sheep (2)
Gene therapy	1. China (1,696)2. United States (1,220)3. Japan (292)4. Germany (258)5. United Kingdom (156)	1. China (2.79%)2. Ireland (2.29%)3. United States (1.57%)4. Israel (1.51%)5. Japan (1.39%)	1. Maxillofacial (1,157)2. Long bones (1,151)- Femur (715)- Tibia (305)3. Calvarial (666)4. Vertebrae (308)	Small animal models (2,405)1. Mice (1,473)2. Rat (912)3. Rabbit (253)Large animal models (169)1. Dog (61)2. Pig (63)3. Goat and sheep (36)
PRP	1. China (457)2. India (428)3. United States (355)4. Italy (214)5. Brazil (162)	1. Iraq (4.30%)2. Indonesia (3.80%)3. Chile (3.40%)4. India (2.90%)5. Egypt (2.57%)	1. Calvarial (65)2. Long bones (62)- Femur (27)- Tibia (22)3. Maxillofacial (34)4. Vertebrae (2)	Small animal models (705)1. Rabbit (399)2. Rat (238)3. Mice (103)Large animal models (313)1. Dog (184)2. Goat and sheep (71)3. Pig (57)

Publication annual average growth rate (2000–2024)

From 2000 to 2024, exosomes showed the highest average annual publication growth rate (113.1%), followed by PDA (68.7%) and graphene (39.8%). Also, materials like OCP and cellulose maintained strong growth above 30%. Following these, materials such as doped bioactive glass, PHB, chitosan, PCL, silk fibroin, and hyaluronic acid, demonstrated solid growth in the 20–30% range. A large group including alginate, cellulose derivatives, stem cells, PEG, PRP, CaCO₃, and chondroitin sulfate showed consistent attention with rates between 15% and 20%. Slightly slower growth, in the 10–15% range, was observed for dextran, gelatin, calcium sulfate, peptide, DCP, BCP, bioactive glass, PLGA, gene therapy strategies, and TCP. The lowest rates, under 10%, belonged to more established materials like collagen, HA, silicate bioactive glass, PLA, BMP, and PMMA. PMMA had the lowest growth at 5.9% (Fig. 40).

FIG. 40.

Publication annual average growth rate from 2000 to 2024.

Five-year annual average growth rate (2020–2024)

From 2020 to 2024, exosome recorded the highest 5-year average publication growth rate at 32.9%, notably above all others, and then alginate with 20.10%. In the 15–20% group, the materials included cellulose derivatives, hyaluronic acid, gelatin, and PDA. The 10–15% group included cellulose, dextran, graphene, chondroitin sulfate, OCP, PCL, and doped bioactive glass, showing moderate but stable growth. Materials with 5–10% growth included chitosan, HA, PLA, PEG, peptide, DCPD, gene therapy techniques, silk fibroin, calcium sulfate, calcium carbonate, bioactive glass, PHB, silicate bioactive glass, and stem cells, reflecting ongoing use with less acceleration. Growth dropped to the under 5% range for PLGA, PRP, BCP, TCP, PMMA, and collagen. The only material with negative growth was BMP (–1.81%), indicating a recent decline in publication focus (Fig. 41).

FIG. 41.

Five-year publication annual average growth rate.

Two-year annual average growth rate (2023–2024)

From 2023 to 2024, dextran led all materials with a sharp 2-year average annual publication growth rate of 43.3%, followed by hyaluronic acid (26.3%), cellulose derivatives (22.1%), and cellulose (21.9%). These materials were the only ones in the 20% and above range. In the 15–20% group, the materials included PLA, doped bioactive glass, alginate, exosome, and gelatin. Materials such as PDA, gene therapy strategies, silicate-based bioactive glass, chitosan, PEG, and bioactive glasses fell into the 10–15% range. The 5–10% group included peptide, PCL, graphene, chondroitin sulfate, CaCO₃, HA, PLGA, stem cells, and silk fibroin. Lower yet positive growth rates under 5% were seen for collagen, PRP, TCP, BCP, and calcium sulfate. Negative growth was observed in BMP, PHB, PMMA, DCP, and OCP, with OCP showing the steepest drop at –28.3% (Fig. 42).

FIG. 42.

Two-year publication annual average growth rate.

Comparison of top five materials across different time periods

Between 2000 and 2024, the fastest-growing materials landscape evolved significantly. Initially, exosomes, PDA, and graphene led growth due to their recent emergence and associated research momentum, alongside established materials like OCP and cellulose in bioactive fields. In the past 5 years, exosome maintained its lead, while PDA and graphene dropped out of the top five, replaced by alginate, cellulose derivatives, hyaluronic acid, and gelatin. By 2023–2024, a notable shift occurred with dextran and hyaluronic acid rising to first and second place. Cellulose and cellulose derivatives remained prominent, and PLA also moved to the top five. These trends are summarized in Table 3.

Table 3.

Top Five Materials Across Different Time Periods

Rank	2000–2024 (long-term)	2020–2024 (5-year)	2023–2024 (2-year)
1st	Exosome	Exosome	Dextran
2nd	PDA	Alginate	Hyaluronic acid
3rd	Graphene	Cellulose derivatives	Cellulose derivatives
4th	OCP	Hyaluronic acid	Cellulose
5th	Cellulose	Gelatin	PLA

Percentage of large animal model

The proportion of large animal models relative to all animal models could possibly serve as an indicator to assess the maturity of a specific research field. A higher ratio may indicate that the field has progressed beyond preliminary stages and that earlier studies using small animal models were sufficiently effective to justify transition to more advanced, clinically relevant large animal testing. This metric can thus reflect both the developmental stage of the research and the translational potential of its findings.

Based on the percentage of large animal model usage, PRP, PMMA, and collagen rank highest, all above 25%, as depicted in Figure 43. It should also be noted that PMMA exhibits a relatively high percentage of studies involving primate models. Close behind, in the 20–25% range, are DCP, BCP, TCP, and chondroitin sulfate. Materials in the 15–20% range include calcium sulfate, cellulose derivatives, OCP, HA, hyaluronic acid, and PLA, showing moderate translational movement. The 10–15% group includes PCL, cellulose, PEG, calcium carbonate, BMP, PLGA, dextran, stem cells, and alginate. However, dextran and calcium carbonate stood out with a notably high proportion of studies involving primate models, with dextran accounting for 1.70% and calcium carbonate for 1.33% of their respective total animal studies. Materials with less than 10% large animal use include silicate bioactive glass, gelatin, chitosan, PHB, peptide, doped bioactive glass, gene therapy strategies, bioactive glass, and silk fibroin. The lowest levels, under 5%, are observed in graphene, exosome, and PDA. This is expected since these materials are relatively new, with research on them beginning years after 2000 rather than earlier.

FIG. 43.

Proportion of large animal models to all animal models.

Small animal models

In small animal models, rats were the most commonly used species across the majority of biomaterial studies. However, notable exceptions include gene therapy techniques, peptides, and stem cell research, where mice emerged as the predominant model. In studies on calcium carbonate, both mice and rats were used equally. Additionally, rabbits were the most frequently employed model in studies involving DCP, PRP, and calcium sulfate.

Bone types

Most biomaterials were predominantly studied in long bones. However, several materials, such as PLGA, collagen, cellulose derivatives, BCP, PRP, gene therapy techniques, and exosomes, showed a higher number of studies in the maxillofacial region. Additionally, OCP, cellulose, and silk fibroin were more frequently associated with the calvarial region.

Discussion

In this study, 35 bone regeneration materials were analyzed, each of which had a minimum of 300 published articles during the 2000–2024 period. Each material followed a distinct trend during this period. Calcium phosphates, which have long been a key focus in this field, their research activity has reached a steady state. The pace of HA research has slowed to a steady state. However, BCP and TCP show signs of decline. OCP continues its downward trend; meanwhile, due to the limited number of OCP articles, this may not be entirely reliable. DCP’s research activity is somewhere between a plateau and a downward trend. Bioactive glasses have emerged as a rapidly growing area, with both silicate-based and doped bioactive glass experiencing an overall upward trajectory, though silicate bioactive glass saw a brief dip after 2017 before rebounding. Natural polymers generally show increasing research activity, with silk fibroin, chitosan, alginate, gelatin, hyaluronic acid, and cellulose seeing increasing research activity. However, collagen research has declined. Chondroitin sulfate and dextran have a low number of articles, leading to fluctuations, and while dextran shows an upward trend, it should be interpreted cautiously. Synthetic polymers present mixed trends; PCL has gained significant attention, while interest in PLGA and PMMA has diminished. PEG experienced a downturn until 2022 before reversing course, while PLA has mostly plateaued aside from a brief dip in 2022 that subsequently recovered. Cellulose derivatives show a slight upward trend, but cellulose derivatives along with PHB have a low number of publications, leading to fluctuations in their trends. Research activity surrounding calcium sulfate and BMPs is on the decline, while calcium carbonate appears to be hovering between a plateau and a gradual upward trend. PRP has been in decline since 2019, whereas stem cell research seems to have reached a steady state. Interest in gene therapy strategies is steadily growing, and peptide research is experiencing a slow but consistent increase. Meanwhile, newer materials like exosomes, polydopamine, and graphene are seeing strong upward trends. It should be noted that these three materials originated during this period rather than in 2000 or before, which has two significant implications. First, their novelty drives increased research focus and trending interest. Second, the initially lower number of publications contributes to a higher average growth rate over time. These factors likely explain why these materials are currently leading in their respective fields.

The variations in research trends and publication volumes among different biomaterials are influenced by multiple factors beyond their ability in bone regeneration. While a material’s effectiveness plays a role, other key aspects also shape research focus and publication rates. One major factor is availability and cost-effectiveness; materials that are widely accessible and economically feasible tend to attract more research due to their practicality for large-scale studies. In contrast, rare or expensive materials may see limited exploration. Another significant consideration is the complexity of fabrication. Materials requiring advanced equipment or intricate processing methods often face barriers to widespread research, resulting in slower growth and lower publication counts. Overall, publication metrics are not solely a direct reflection of a material’s properties, but rather a multifaceted outcome influenced by technological, economic, and infrastructural considerations.

It should be noted that the slight decline in the total number of published bone regeneration articles from 2021 to 2023 may be linked to shifts in research priorities, changes in funding, or project delays caused by the COVID-19 pandemic.^19,20 With the end of the pandemic and the revival of bone regeneration research, studies in this field have gained renewed momentum.

Global interest rates

Countries with fewer than 500 publications on bone repair were excluded from analysis to prevent overexaggerated interest rates in low-output countries. Most excluded countries were in Africa and Central Asia. Orthopedic research in Africa and Central Asia faces significant barriers. In Africa, challenges include limited funding, heavy clinical workloads, and insufficient research training. Weak institutional support, a lack of research infrastructure, and a predominant focus on infectious disease research further restrict orthopedic advancements.²¹ Many surgeons also prioritize private practice, limiting engagement in research.²¹ In Central Asia (Kazakhstan, Uzbekistan, Tajikistan, Turkmenistan, and Kyrgyzstan), productivity is hindered by insufficient funding, lack of dedicated research centers, and insufficient training in research methods.²² Similar to Africa, a strong focus on infectious disease research often overshadows efforts in orthopedics.²²

China led global bone regeneration research in publication volume across nearly all materials. The United States consistently ranked second in publication count but showed considerably lower interest rates across most materials, indicating a broader yet less concentrated research approach. In contrast, countries like Portugal, Iran, South Korea, Singapore, and Indonesia frequently appeared among the top in both absolute and relative terms, especially in areas such as PCL, gelatin, stem cells, doped bioactive glass, and various natural polymers.

The level of interest in certain materials varies across countries due to several key factors. Availability and cost-effectiveness play a crucial role, as nations with abundant natural resources or lower production costs may prioritize specific materials for research. Additionally, the complexity of fabrication influences accessibility; materials requiring advanced equipment or intricate processing methods often face barriers to widespread study, limiting their adoption in regions with less-developed technological infrastructure. Regulatory frameworks also shape research priorities, as stringent policies can either encourage or restrict the exploration of certain materials based on environmental, safety, or strategic concerns. For instance, our findings indicate that Iran and China showed the highest interest in stem cell research, which may be influenced by national policies. Both countries have relatively permissive or flexible regulations regarding stem cell studies.^23–26 Indonesia, Portugal, Malaysia, Iran, and Romania have shown high interest in CaP materials, and one possible reason could be their cost-effectiveness, especially naturally derived CaP,²⁷ making them a particularly attractive option for biomedical applications in regions where cost-effective materials are prioritized in scientific advancements. Similarly, cellulose has drawn significant research attention in Egypt, Romania, Pakistan, Malaysia, and Iran. Cellulose is a widely available biomaterial found across the globe.²⁸ Its affordability could be a factor explaining this global interest rate. PRP is also widely studied in Iraq, Indonesia, Chile, India, and Egypt, and its availability, low cost, and minimal equipment requirements could be one of the reasons for its prominence in these regions.^29,30 In the case of bioactive glasses, Finland displayed significantly higher interest rates compared with other countries. One probable reason for this trend is the presence of BonAlive® Biomaterials Ltd. in Finland the company behind S53P4 bioactive glass, a material predominantly used in Finnish bioactive glass research.³¹ Likewise, Thailand exhibited the highest interest rates in silk fibroin research. This could be due to its rich diversity of domesticated Bombyx mori races, particularly the Thai native silkworm (Nangnoi-Sisaket 1).³² In addition, Thai silk fibroin has been widely explored for biomedical applications.³³ While the structural components of silk fibroin from Thai, Japanese, and Chinese Bombyx mori are identical,³⁴ Thai silk fibroin has some superior properties, such as its higher hydrophobic amino acid content and higher adsorption.^35,36 There appears to be a greater tendency to use chitosan in countries situated near ocean basins, such as Indonesia, Portugal, Iran, and Malaysia. Chitosan is derived from chitin, a polysaccharide found in the exoskeletons of marine crustaceans like shrimp and crabs.³⁷ Nations with well-established seafood industries (e.g., Indonesia and Malaysia) benefit from local availability of chitin-rich waste,³⁸ making chitosan a more cost-effective and accessible resource for biomedical research.

Animal models

As seen in Figure 41, the proportion of large animal models relative to all animal models varies from 27.63% in PRP to 2.69% in PDA. As the field expands and the number of publications on a specific material increases, the utilization of large animal models tends to grow accordingly, because small animals are practical models for early stages of therapy evaluation.^39,40 Aside from that, small animal models always constitute a higher percentage due to their ethical advantages, cost-effectiveness, and ease of handling.³⁹ Their affordability and suitability for bone research make them serve as an essential foundation before transitioning to large-scale studies.

The rat model was the most frequently used small animal model across most materials. This is likely due to its cost-effectiveness and practicality.⁴⁰ Additionally, its larger size compared with mice makes it ideal for studies involving surgical procedures and defect creation, making results more reliable and reproducible.³⁹

In some cases, rabbits were more commonly used than rats and mice, particularly in PRP, DCP, and calcium sulfate studies. While this difference is insignificant in DCP and calcium sulfate, it is notably significant for PRP. This preference likely arises from the ease of blood collection in rabbits compared with rats and mice. A relatively large blood sample can be withdrawn from rabbits without compromising their health, making them more suitable for PRP preparation.⁴¹

In certain cases, the mouse emerged as the most frequently used small animal model, particularly in gene therapy strategies. This preference can be attributed to the mouse’s well-known and extensively researched genetic map and the long availability of genetic manipulation tools since the 1980s.^42,43

Among the large animal models, dogs were the most frequently used species across most biomaterials. The second most commonly utilized large animals were either pigs or goats and sheep. The variation in model selection likely reflects geographical and socioeconomic factors influencing animal availability. For instance, goats and sheep are more prevalent in regions such as Australia, New Zealand, the Middle East, and North Africa,^44,45 whereas pigs are more accessible and commonly used in Europe and North America,^46,47 thus making these regions more inclined to adopt pig models in research. Overall, goats and sheep were used more frequently than pigs in 19 biomaterials, whereas pigs surpassed goats in 16 biomaterials. This preference for sheep and goats may be due to practical considerations. While pigs have been utilized in bone regeneration studies, their handling requirements often deter researchers. In contrast, sheep are the most common choice for segmental bone defect studies.⁴⁸ Their mature body weight aligns with adult humans, facilitating clinical translation.⁴⁹ Additionally, the mechanical loading of ovine hind limbs is well documented, approximately half of that in humans during walking,⁵⁰ further supporting translational research.⁴⁸ Moreover, sheep share similar metabolic and bone remodeling rates with humans,⁵¹ making them a valuable model.

Bone types

Most biomaterials have been predominantly studied in long bones, particularly the femur and tibia, due to their relevance in fracture healing models. These bones are commonly selected as they effectively recapitulate fracture dynamics,⁵² closely mimicking real-world traumatic fractures, which frequently occur in long bones.⁵³ The preference for the femur and tibia stems from their high susceptibility to fractures and their weight-bearing function, which influences mechanical stability and healing responses.⁵² The choice of defect location in animal models is a crucial factor in determining healing dynamics over time, with each bone presenting unique indications for defect creation.⁵⁴

The selection of an appropriate animal model and a clinically relevant bone defect is fundamental to the success of translational research in bone regeneration studies.^48,55 An ideal model should replicate clinical conditions, including mechanical loading, defect fixation, and the native biology of bone healing, while also balancing practical considerations such as cost, ethical responsibility, and technical feasibility.^48,49,55 This choice is pivotal, as both the location and type of defect profoundly influence healing outcomes due to site-specific biological differences.^55,56 Inadequate model selection risks generating data that lack clinical relevance, ultimately wasting resources and delaying the translation of promising therapies to patients. To support researchers in making informed decisions, Table 4 summarizes the advantages, disadvantages, implantation sites, and critical defect sizes of the most commonly used animal models.

Table 4.

Key Characteristic of Most Common Animal and Bone Defect Models for Bone Regeneration Studies

Animal species	Most commonly used model construction site	Critical value size	Advantages	Disadvantages	References
Mouse	Calvarial	3–8 mm in diameter	Widely used, standardized protocols Cost-effective Easy feeding Rapid healing High genetic similarity	Very small size, high surgical technique requirements Low reproducibility Biomechanical and serum marker evaluation is difficult Unsuitable for Haversian system studies Fixation is nearly impossible External callus formation rare in stable models, limiting similarity to human healing	^57–63
	Femur	About 25% of the length of the femur, 2–5 mm segmental
	Tibia	3 mm segmental
Rat	Calvarial	5–8 mm in diameter	Widely used, standardized protocols Cost-effective Easy feeding Tolerate surgical procedures well Convenient for biomechanical and serum marker assessment Healing time relatively short	Skeletal properties differ markedly from those of humans Unsuitable for Haversian system studies Mechanical stability is difficult to control, fixation is often insufficient High variability in osteoporotic animals External callus formation inconsistent, dependent on stability Bone metabolism is more robust than human bone	^57–65
	Mandible	4 mm in diameter
	Mandible	Box bone defect 6 × 2 mm
	Femur	4–10 mm segmental
	Tibia	3–8 mm segmental
Rabbit	Mandible	8–15 mm in diameter	Widely used, standardized protocols Gentle temperament, easy feeding Low surgical technique requirements Suitable for biomechanical testing Blood sampling, easy to perform Haversian system closely resembles humans Fast skeletal remodeling Stable models allow reproducible healing outcomes	Biomechanical properties differ significantly from human bone due to their different hopping and walking patter Some fracture sites (e.g., fibula) not clinically representative Frequent implant failures in certain models Adverse events reported in distal femur studies External callus formation rare, limiting similarity to human healing	^{57,58,62–64,66,67}
		10 × 5 × 3 mm segmental
		10–13 × 9–10 mm full thickness square bone defect
		Box-shaped bone defect of 8 × 3 × 2 mm
	Femur	Larger than 6 mm in diameter
	Femur	10–20 mm segmental
	Tibia	8 mm in diameter
	Tibia	10–15 mm segmental
	Ulna	15–20 mm segmental
	Radius	15 − 20 mm segmental
	Calvarial	8 − 15 mm in diameter
Dog	Femur	20–40 mm segmental	Adult canine bone closely matches human bone in structure and strength Similar physiological traits and fracture mechanics to humans Specimens (blood, urine, bone) are easily obtainable	Ethical concerns restrict wider use in research Bone remodeling differs from human biomechanical reconstruction Limited literature base compared with small animals	^{57,58,62–64,66–70}
	Femur	A 15 × 10 mm saddle-type bone defect
	Radius	20–30 mm segmental
	Mandible	5–25 mm in diameter
		20 mm segmental
		4 × 5 mm box-type defect
	Ulna	20–25 mm segmental
Sheep and goat	Tibia	30–50 mm segmental	Calm temperament, easy to handle Relatively inexpensive Close anatomical similarity with humans Body weight similar to humans Available in large numbers Early weight-bearing after surgery, well-tolerated procedures Mechanical conditions can be precisely controlled Most commonly used animal species for segmental bone defects	Limited literature base compared with small animals Significantly higher trabecular bone density and subsequently greater bone strength Larger amount of bone ingrowth than humans Knee contact areas are different Prone to illness	^{57,58,62–64,66,67,71–75}
	Tibia	2–2.5 times the diameter of the bone
	Mandible	35 mm segmental
Pig	Calvarial	10–12 mm in diameter	Close anatomical similarity with humans Specimens (blood, urine, bone) are easily obtainable Bone density and bone regeneration rate closely match those of humans	High price Not easy to feed Bone remodeling differs from human biomechanics	^{57,58,62–64,70,76}
	Mandible	6 mm in diameter
	Mandible	5 cm³ volume of bone defect
	Femur	30 mm segmental
	Tibia	30 mm segmental

Strength and limitations

This study presents several strengths, including an extensive evaluation period from 2000 to 2024 and a comprehensive comparative analysis of diverse biomaterials, enhancing the relevance and applicability of its findings. Additionally, the incorporation of meaningful indicators, such as clinical trial percentages, animal model types, and anatomical application sites, provides deeper insights. Furthermore, adjusting the global interest rate for specific materials based on their proportion of total bone regeneration publications per country offers a refined approach, leading to more insightful results. Given that countries such as the United States and China consistently lead in absolute publication counts across most scientific fields,⁷⁷ direct comparisons based on raw numbers alone may obscure a country’s relative emphasis on specific bone regeneration materials. By applying this adjustment, the analysis better captures national research interest independent of overall scientific productivity or population size. A similar adjustment was applied to publication trends over time. This normalization accounts for the exponential growth of scientific output, as described by Price’s theory of scientific growth, which suggests that research publications tend to double every 10–15 years.^78,79 Without this adjustment, raw publication counts may primarily reflect overall expansion in scientific publishing rather than a targeted increase in interest in specific materials. This adjustment ensured a more accurate representation of shifts in research focus.

Despite its contributions, this study has several limitations. First, the vast number of publications on bone regeneration made manual screening impractical. As a result, there is a potential risk of including irrelevant studies. However, rigorous keyword refinement and relevance checks were implemented to mitigate this issue. Second, the analysis was confined to the Scopus database, which, while offering broad coverage and high-quality indexing, may have excluded relevant studies from other sources. Third, the global interest rate analysis considered only countries with over 500 publications on bone regeneration between 2000 and 2024. This threshold prevented inflated interest rates in countries with low publication counts but may have excluded emerging contributors, affecting global inclusivity. Fourth, the search was restricted to titles, abstracts, and keywords rather than full-text content, potentially omitting relevant studies. However, this approach minimized the inclusion of unrelated results, which is more likely in full-text searches without manual screening. Moreover, it is unlikely that an article focusing on a specific biomaterial would fail to mention that biomaterial in its title, abstract, or keywords. Last, the animal and bone model analyses did not cover all species or anatomical sites. Nevertheless, the study prioritized the most frequently examined and clinically relevant examples to maintain practical significance.

Conclusion

This review analyzes trends of 35 bone regeneration materials, revealing various research patterns. This study observed growing interest in certain materials (e.g., bioactive glasses, natural polymers), declining attention to others (e.g., BMPs), and certain materials remained at a stable research level (e.g., calcium phosphates, PRP, stem cells). China and the United States led global publication numbers across nearly all materials, while countries like Portugal, Iran, South Korea, Singapore, and Indonesia consistently appeared among the highest in interest rates.

Authors’ Contributions

A.D.: Conceptualization, data curation, formal analysis, methodology, project administration, software, visualization, and writing—original draft. S.F.-M. and M.M.D.: Conceptualization, methodology, supervision, validation, and writing—review and editing.

Footnotes

Acknowledgments

The authors would like to express immense gratitude to Dr. Mahtab Maghsudlu and Dr. Alimohammad Yavari for their valuable assistance throughout the completion of this review.

Funding Information

This research was conducted without any financial support.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Confirmation Statement

The authors are from the University of Tehran (Tehran, Iran), where education and research are the primary functions.

Disclosure Statement

The authors declare no conflicts of interest.

Supplemental Material

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